Amidinourea local anesthetics

ABSTRACT

A method for producing local anesthetic action in a patient by administering amidinoureas.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a division of our co-pending application Ser. No. 671,762 filedMar. 30, 1976, now abandoned, which is a continuation-in-part of ourco-pending application Ser. No. 558,187 filed Mar. 31, 1975, now U.S.Pat. No. 4,060,635 issued Nov. 29, 1977.

SUMMARY OF THE INVENTION

This invention describes a new class of chemical compounds and theprocess for their preparation. This invention also describes a newmethod for producing local anesthetic and anti-arrhythmic actions. Thisinvention further provides valuable pharmaceutical preparations whichare effective for producing local anesthetic and anti-arrhythmicactions. This invention further describes a class of chemical compoundscalled amidinoureas and the same possess an effective degree of activitywhich is capable of producing local anesthetic and anti-arrhythmicproperties in mammals.

BACKGROUND OF THE INVENTION

Local anesthetics block nerve conduction when applied locally to nervetissue. They may act on any part of the nervous sytem and on every typeof nerve fiber or they may act selectively between different types ofnervous tissue such as central nervous tissue or peripheral nervoustissue or myelinated or non-myelinated fibers. The advantage with usefullocal anesthetics is that their action is reversible and nerve functionis restored with no evidence of structural damage to nerve fibers orcells. Continued studies have been carried out in research to developdrugs which would have all the desirable properties of a good localanesthetic agent. Such properties would necessarily be non-irritating tothe tissue with which it is in contact or cause any permanent damage tonerve structure. Further, its sustemic toxicity should be low. The ideallocal anesthetic should be effective regardless whether it is injectedinto the tissue or applied locally to mucous membranes. The time foronset should also be as short as possible while its action should lastlong enough for the need indicated, and the recovery period should beone which is of a suitable duration.

Anti-arrhythmic agents have been long sought by the researchers. Theprincipal anti-arrhythmic drugs of long established usefulness arequinidine and procainamide. More recently lidocaine, phenytoin andpropranolol have been found to be helpful in establishing certainanti-arrhythmic disorders. Each of these agents, however, has been foundto have certain drawbacks and great care must be used when they areemployed for the treatment of arrhythmic disorders. The idealanti-arrhythmic agent would be one having a minimal amount of sideeffects while at the same time being orally active, typical side effectbeing myocardial depression and CNS deficit. The most serious form ofarrhythmia is fibrillation and a high degree of protection against thisparticular disorder would be most beneficial.

We have unexpectedly found potent anti-arrhythmic and local anestheticagents.

We have unexpectedly found a class of chemical compounds which haveanti-arrhythmic and local anesthetic properties without accompanyingside effects which are common with these agents.

We have further found unexpectedly that amidinourea compounds areeffective anti-arrhythmic agents which act orally.

We have also unexpectedly found a means of providing protection againstfibrillation.

We have also unexpectedly found that administration of amidinoureas is asimple and effective method for the treatment of anti-arrhythmicdisorders.

We have still further found effective local anesthetic agents which arenon-irritating to the tissue, do not cause permanent damage to theirstructure, their sustemic toxicity is low, and they are effective whenapplied by injection into the tissue or applied locally. These agentshave also been found to have a desirable onset period while their actionmay be extended for periods of time depending on the use intended.

DESCRIPTION AND PREFERRED EMBODIMENTS

This invention describes a novel class of chemical compounds of theformula ##STR1## where: R₂, R₃, R₄, R₅ and R₆ may be the same ordifferent and are; hydrogen,

halo,

loweralkyl,

haloloweralkyl,

nitro,

amino, acylamino,

hydroxy,

aralkyloxy or

loweralkoxy;

R₇, r₈, r₉ and R₁₀ may be the same or different and are:

hydrogen,

alkyl,

alkenyl,

alkynyl,

cycloalkyl,

cycloalkenyl,

cycloalkylloweralkyl,

alkoxyloweralkyl,

aralkoxyloweralkyl or

aralkyl;

R₇ and R₈ together and R₉ and R₁₀ together may form a 5-7 atom ringwhich may further include 0-1 hetero atoms of N, O or S;

R_(n) is hydrogen or loweralkyl provided at least one of R₇, R₈, R₉ andR₁₀ is other than hydrogen; and

the non-toxic acid addition salts thereof.

In any discussion of the true structure of an amidinourea, tautomerismmust be considered. It should be clear to anyone skilled in the art thatthe amidinourea sidechain can be legitimately represented in any one ofseveral tautomeric and geometric modifications.

The total number of possible variations in structure is quite high, butit is true to say that these variations can and, to some extent, dooccur when these compounds are in solution.

One form may predominate over another depending upon the degree andlocation of substitution and on the nature of the solvent. The rates ofconversion of one tautomer to another will depend upon the nature of thesolvent, the degree of hydrogen bonding permitted, the temperature andpossibly other factors (such as pH, trace impurities and the like).

To illustrate what is meant by this, a number of likely structures arehere shown for just one of the compounds in this invention. ##STR2##

Of course, other types of structures are possible such as those withhydrogen bonding. ##STR3##

No attempt is made to exhaust the possible structures, for these arelegion. The structures given are representative of the kind ofphenomenon we are trying to describe and are encompassed within thescope of this invention.

It is predictable that in physiological conditions, any or all of thesestructures may exist or even predominate at the sites at which thesemolecules operate.

Tautomerism, of course, by definition only applies to protons and not toother groups. Thus, in the example given, free conversion betweenstructures occurs smoothly by transference of a single proton. At a timewhere other substituents are concerned, tautomerism is to just thatextent ruled out. For example where there are no protons at all becauseof full substitution, only one structure may be reasonably said to existsuch as: ##STR4##

Compounds of this invention which are preferred include those where:

R₂, r₃, r₄, r₅ and R₆ are hydrogen,

halo,

loweralkyl,

haloloweralkyl,

nitro or

loweralkoxy; and

R₇, r₉ and R_(n) are hydrogen or loweralkyl;

R₈ and R₁₀ are hydrogen or alkyl, alkenyl, alkynyl, alkoxyloweralkyl andaralkoxyalkyl provided R₇, R₈, R₉ and R₁₀ are not all hydrogen at thesame time; and

R₇ and R₈ together and R₉ and R₁₀ together are alkylidenyl.

The more preferred compounds of this invention include those where:

R₂ is hydrogen or loweralkyl;

R₃ and R₅ are hydrogen;

R₄ is hydrogen,

loweralkyl or halo

R₆ is hydrogen,

loweralkyl, nitro,

alkoxy or halo;

R₇, r₉ and R_(n) are hydrogen or loweralkyl; and

R₈ and R₁₀ are hydrogen or alkyl,

alkenyl,

alkynyl,

alkoxyloweralkyl or

aralkoxyloweralkyl; provided R₇, R₈, R₉ and R₁₀ are not all hydrogen atthe same time;

R₇ and R₈ together and R₉ and R₁₀ together are alkylidenyl.

The most preferred compounds of this invention are those where;

R₂ is hydrogen, methyl or ethyl;

R₃ and R₅ are hydrogen;

R₄ is hydrogen, mthyl, ethyl, chloro or bromo;

R₆ is hydrogen,

methyl, ethyl

nitro,

methoxy,

ethoxy,

chloro

bromo or

fluoro;

R_(n) is hydrogen,

methyl or ethyl, and

R₇, r₈, r₉ and R₁₀ are hydrogen,

methyl,

ethyl,

propyl,

i-propyl,

butyl,

i-butyl,

sec-butyl,

t-butyl,

pentyl,

hexyl,

heptyl,

allyl,

propargyl,

methoxyethyl

ethoxyethyl

benzyloxyethyl; provided R₇, R₈, R₉ and R₁₀ are not all hydrogen at thesame time; and

R₇ and R₈ together and R₉ and R₁₀ together are tetramethylene,pentamethylene and hexamethylene.

A special embodiment of this invention comprises compounds which have:

R₂ -loweralkyl substitution;

R₂, r₆ -diloweralkyl substitution;

R₂, r₆ -loweralkyl, alkoxy substitution;

R₂, r₆ -loweralkyl, halo substitution;

R₂, r₆ -alkyl, nitro substitution;

R₂, r₄, r₆ -triloweralkyl substitution, or

R₂, r₄, r₆ -loweralkyl, dihalo substitution.

A further special embodiment of this invention comprises compounds whichhave:

R₂, r₆ -dihalo substitution.

A further special embodiment of this invention comprises compounds whichhave:

R₇, r₈, r₉ and R₁₀ are hydrogen or loweralkyl substitution all are nothydrogen at the same time;

R₇, r₈ and R₉ are hydrogen or loweralkyl and R₁₀ is an alkyl, alkenyl oralkynyl group from 3 to 7 carbon atoms; or

R₇, r₈ and R₉ are hydrogen or loweralkyl and R₁₀ is anaralkoxyloweralkyl group.

This invention further describes a novel method for producing localanesthetic and anti-arrhythmic properties by the administration of acompound of the formulae: ##STR5## where: R₂, R₃, R₄, R₅ and R₆ may bethe same or different and are:

hydrogen,

halo,

loweralkyl,

haloloweralkyl,

nitro

amino, acylamino or

loweralkoxy and

R_(n) is hydrogen or

loweralkyl;

R₇, r₈, r₉ and R₁₀ are:

hydrogen,

alkyl,

alkenyl,

alkynyl,

cycloalkyl,

cycloalkenyl,

cycloalkylloweralkyl,

alkoxyloweralkyl

aralkoxyloweralkyl or

aralkyl;

R₇ and R₈ together and R₉ and R₁₀ together may form a 5-7 atom ringwhich may further include 0-1 hetero atoms of N, O or S; and

the non-toxic acid addition salts thereof.

It is well known in the pharmacological arts that non-toxic acidaddition salts of pharmacologically active amine compounds do not differin activities from their free base. The salts merely provide aconvenient solubility factor.

The amines of this invention may be readily converted to their non-toxicacid addition salts by customary methods in the art. The non-toxic saltsof this invention are those salts the acid component of which ispharmacologically acceptable in the intended dosages; such salts wouldinclude those prepared from inorganic acids, organic acids, higher fattyacids, high molecular weight acids, etc., and include such as:

    ______________________________________                                        hydrochloric acid,   succinic acid,                                           hydrobromic acid,    glycolic acid,                                           sulfuric acid,       lactic acid,                                             nitric acid,         salicylic acid,                                          phosphoric acid,     benzoic acid,                                            methane sulfonic acid,                                                                             nicotinic acid,                                          benzene sulfonic acid,                                                                             phthalic acid,                                           acetic acid,         stearic acid,                                            propionic acid,      oleic acid,                                              malic acid,          abietic acid, etc.                                       ______________________________________                                    

The nomenclature applied to the compounds of this invention is based onthe urea moiety as follows: ##STR6##

The term "loweralkyl" refers to an alkyl hydrocarbon group from 1 to 5carbon atoms which may be straight chained or branched while "alkyl"refers to an alkyl hydrocarbon group which may have as many as tencarbon atoms.

The term "alkenyl" refers to an alkenyl hydrocarbon chain having 3-7carbon atoms.

The term "alkynyl" refers to an alkynyl hydrocarbon chain having 3-7carbon atoms.

The term "cycloalkyl" refers to a cycloalkyl group having 3-7 carbonatoms.

The term "cycloalkenyl" refers to a cycloalkenyl group having 5-7 carbonatoms.

The "loweralkoxy" radical signifies an alkoxy group containing from 1 toabout 5 carbon atoms which may be straight chained or branched.

The preferred "aryl" group is phenyl.

The preferred "aralkyl" groups are benzyl and phenethyl.

The preferred "haloloweralkyl" group is trifluoromethyl.

The preferred "haloloweralkoxy" group is trifluoromethoxy.

The compounds of this invention may be prepared by the following generalsynthesis:

It is convenient to generate the substitute guanidine in situ byhydrolyzing a salt of the guanidine with base in the reaction medium.The appropriate isocyanate is then added dropwise into the well-stirredreaction mixture. Condensation of a substitutedphenyl isocyanate(prepared from an aniline and phosgene in the customary manner) withguanidine results in a 1-substitutedphenyl-3-amidinourea. The reactionis carried out in a polar medium using solvents such asdimethylformamide, tetrahydrofuran, etc. ##STR7##

These compounds may also be prepared by degradation of the correspondingbiguanide. When a 1-substitutedphenylbiguanide compound is hydrolyzed inacid at raised temperature then the resultant product is1-substitutedphenyl-3-amidinourea. This reaction is preferably carriedout using hydrochloric acid and the reaction time and reactiontemperature will of course depend on the particular biguanide used andthe concentration of the acid present. In general, the more concentratedacids will not require high temperatures or long periods of reactiontime. ##STR8##

When it is desired to have R_(n) substitution at the N-3 the startingmaterial of course will be an aniline having N-alkyl substitution.Reaction with phosgene results in the carbamoyl chloride which is thenreacted with the substituted guanidines to prepare the amidinourea.##STR9##

The starting anilines are either known, may be prepared by knowntechniques or reference to the preparation is shown. Thus, chlorinationor bromination of an acetanilide or aniline may be carried out in aceticacid, or in the presence of a small amount of iodine dissolved in aninert solvent such as carbon tetrachloride. A solution of chlorine orbromine is then added while the temperature is held near 0° C.Iodination may also be carried out by known methods using iodinemonochloride (Cl I).

Alkylation may be carried out on an acetanilide using an alkyl halideand aluminum chloride under Friedel-Crafts conditions to obtain desiredalkyl substitution.

Nitration may be carried out using fuming nitric acid at about 0° C.

A nitro compound may be hydrogenated to the corresponding amine whichmay then be diazotized and heated in an alcohol medium to form thealkoxy compound.

An amino compound may also be diazotized to the diazonium fluoroboratewhich is then thermally decomposed to the fluoro compound.

Diazotization followed by a Sandmeyer type reaction may yield the bromo,chloro or iodo compound.

A chloro, bromo or iodo compound may also be reacted withtrifluoromethyliodide and copper powder at about 150° C. indimethylformamide to obtain a trifluoromethyl compound [TetrahedronLetters: 47, 4095 (1959)].

Reactions may also be carried out at other stages of synthesis dependingon the substituents present and the substituents desired and variouscombinations of the foregoing reactions will be determined by oneskilled in the art in order that the desired product results. Thus, aphenylamidinourea may be halogenated or nitrated as above, etc.

The biguanide starting materials are also either known, may be preparedby known procedures or may be prepared by the following generalsynthesis:

Condensation of cyanoguanidine and an aniline in the presence of anequimolar amount of a mineral acid results in the correspondingphenylbiguanide: ##STR10##

This reaction is preferably carried out on the aniline salt either in apolar medium or neat and using increased temperatures. The appropriatelysubstituted product may be prepared by the reactions above when the sameare also carried out in the biguanide or amidinourea.

We have found that the compounds of this invention exercise a usefuldegree of local anesthetic and anti-arrhythmic activity in mammals; assuch they are effective in producing local anesthetic actions and in thetreatment or conversion of known arrhythmias or for the protectionagainst fibrillation. In general, the compounds of this invention areindicated for a wide variety of mammalian conditions where the use of alocal anesthetic is necessary. These compounds when used as ananti-arrhythmic agent are found to be effective against arrhythmias ofatrial and ventricular origin. For these purposes, the compounds of thisinvention are normally administered parenterally and/or topically aslocal anesthetic agents and they may also be administered orally orparenterally for anti-arrhythmic indications.

Orally, they may be administered in tablets, aqueous or oilysuspensions, dispersible powders or granules, emulsions, hard or softcapsules, or syrups or elixirs. The term "parenteral" as used hereinincludes subcutaneous, intravenous, intramuscular or intrasternalinjections or infusion techniques.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apharmaceutically elegant and palatable preparation. Tablets whichcontain the active amidinourea ingredient in admixture with non-toxicpharmaceutically acceptable excipients are suitable for the manufactureof tablets. These excipients may be, for example, inert diluents, forexample, calcium carbonate, sodium carbonate, lactose, calcium phosphateor sodium phosphate; granulating and disintegrating agents, for example,maize starch or alginic acid; binding agents, for example, starch,gelatin or acacia; and lubricating agents, for example, magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with an oilmedium, for example, arachis oil, liquid paraffin or olive oil.

Aqueous solutions containing the active amidinourea form a furtherembodiment of this invention. Excipients suitable for aqueoussuspensions, may be employed if desired. These excipients are suspendingagents, for example, sodium carboxymethyl-cellulose, methyl-cellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidine, gumtragacanth and gum acacia; dispersing or wetting agents may be anaturally occurring phosphatide, for example, lecithin; or condensationproducts of an alkylene oxide with fatty acids, for example,polyoxyethylene stearate; or condensation products of ethylene oxidewith long-chain aliphatic alcohols, for example,heptadecaethyleneoxy-cetanol; or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol, for example,polyoxyethylene sorbitol mono-oleate; or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example, polyoxyethylene sorbitan monooleate. The saidaqueous suspensions may also contain one or more preservatives, forexample, ethyl, or n-propyl, p-hydroxy benzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil, such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents, such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example, sweetening, flavoring andcoloring agents, may also be present.

The compounds of this invention may also be in the form of oil-in-wateremulsions. The oily phase may be a vegetable oil, for example, olive oilor arachis oils, or a mineral oil, for example, liquid paraffin ormixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example, gum acacia or gum tragacanth,naturally-occurring phosphatides, for example, soya bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example, sorbitan mono-oleate. The emulsions may alsocontain sweeping and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, sorbitol or sucrose. Such formulations may alsocontain a demulcent, a preservative and flavoring and coloring agents.The pharmaceutical compositions may be in the form of a sterileinjectionable preparation, for example, as a sterile injectable aqueoussuspension. This suspension may be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agentswhich have been mentioned above. The sterile injectable preparation mayalso be a sterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, for example, as an aqueoussolution buffered to a pH of 4.0 to 7.0 and made isotonic with sodiumchloride.

Further, the active amidinourea may be administered alone or inadmixture with other agents having the same or different pharmacologicalproperties.

Further, these compounds may be tableted or otherwise formulated fororal use so that for every 100 parts by weight of the composition, thereare present between 5 and 95 parts by weight of the active ingredient.The dosage unit form will generally contain between about 1 mg. andabout 500 mg. of the active ingredients of this invention. The preferredunit dose is between about 10 mg. and about 100 mg. The compositions maybe taken 1-8 times daily depending on the dosage unit required.

The dosage regimen in carrying out the methods of this invention is thatwhich insures maximum therapeutic response until improvement is obtainedand thereafter the minimum effective level which gives relief. Thus, ingeneral, the dosages are those that are therapeutically effective in thetreatment of arrhythmias and producing local anesthetic actions. Ingeneral, the oral daily dose can be between about 0.1 mg/kg and 70 mg/kg(preferably in the range of 0.5-50 mg/kg/day), bearing in mind, ofcourse, that in selecting the appropriate dosage in any specific case,consideration must be given to the patient's weight, general health,age, and other factors which may influence response to the drug.

Parenteral administration may be carried out using comparative dosagestaken from the oral compositions. In general, the parenteral dosage willbe less than the oral dose and normally within the range of 1/2 to 1/10the oral dose but, of course, this would depend on the absorptioncharacteristics of the compound employed. Dosages would be in thecustomary manner; however, in general, parenteral administration may becarried out neat or the compound may be utilized with a sterile vehicleas mentioned above. Dosage unit forms between 1 mg. and 500 mg. andpreferably in the range of 10 mg. and 100 mg. are useful. The dailyparenteral dose would be between 0.1 mg/Kg/day and 70 mg/Kg/day andpreferably in the range of 0.5 mg/Kg and 50 mg/Kg/day.

These compounds may further be formulated for topical administration inthe usual manner. Preferred formulations in the form of a gel or pasteor the like may contain the active ingredient in the range of 0.1-10% byweight of the composition.

Various tests can be carried out in animal models to show the ability ofthe amidinoureas of this invention to exhibit reactions that can becorrelated to anti-arrhythmic properties and local anesthetic activityin humans. The following tests show the ability of the compounds of thisinvention to produce local anesthetic actions in animals and are knownto correlate well with local anesthetic activity in humans. These areconsidered to be standard tests used to determine local anestheticproperties. This correlation can be shown by the activities of compoundsknown to be clinically active. In view of the results of these tests,the amidinoureas of this invention can be considered to be localanesthetic agents.

The following tests are used in order to determine the effectiveness ofthe amidinoureas of this invention and their anti-arrhythmic properties.

Harris Dog Induced Arrhythmia

In 1950, Harris published a technique for induction of acute myocardialinfarction in dogs which has become accepted as a useful method forstudying the efficacy of anti-arrhythmic agents. Generally, ventriculararrythmias arise 4 to 8 hours after acute myocardial infarction andpersist for 48 to 72 hours. It is felt that the arrythmias originate insubendocardial Purkinje cells within or near the site of the infarctionand are due to enhanced automaticity within these cells. We haveemployed this model for the evaluation of oral anti-arrythmic efficacyof the amidinoureas of this invention.

Methods

Healthy male mongrel dogs 9.5-15 kg. were anesthetized with intravenoussodium pentobarbital (30 mg/kg) and the trachea was intubated andrespired with room airwith a Harvard respirator. Under asepticconditions, the chest was opened through a small left thoracotomy at thefourth or fifth intercostal space and the pericardium incised near theleft atrial appendage. The left anterior descending coronary artery wasisolated approximately 5-10 mm distal to the left atrial appendagewithout traumatizing the associated coronary vein. A double ligature waspassed under the coronary artery. One of the ligatures was firmly tiedaround a 20 g. needle barrel overlying the coronary artery, and theneedle immediately extracted. This procedure results in a 20-50%constriction of the coronary artery at the site of the ligature. After20 minutes, the second ligature was tied in order to completely occludethe distal portion of the left anterior coronary artery. The lungs werethen expanded. The chest wall was closed and the thoracic cavityevacuated. The dogs were allowed to recover from anesthesia withsupplementary morphine or Tranvet (propiopromazene HCl) administered asneeded to prevent unnecessary pain. Antibiotics were givenprophylactically.

Eighteen to 24 hours after surgery, the dogs were placed in cages in aquiet environment with water constantly available. At this time the dogswere able to walk freely around the cage and showed no signs of obviousdiscomfort. The Lead II electrocardiogram was monitored continuously andrecorded on a Beckman Dynograph recording system. Recordings were madeon a scheduled basis before and after administration of gelatin capsulescontaining the amidinourea (10 mg/kg) or placebo. Normal and abnormalbeats were counted and expressed as a ratio of normal beats/total beatsper unit time. Only beats of sinoatrial origin were considered normal.

The dogs were generally given the first capsule after recording the EKGfor 40-60 minutes. After three hours a second capsule was given and EKGswere monitored for an additional three hours. The dogs were then fed.Forty-eight hours after surgery, the dogs were again monitored accordingto the schedule employed on the first day.

At the end of the second day, the dogs were sacrificed with anintravenous overdose of sodium pentobarbital. Hearts were extracted andexamined to determine the size and area of the induced infarct.

In view of these tests it is concluded that oral administration ofamidinoureas of this invention produce a significant reduction in theincidence of ventricular ectopic rhythm in dogs with myocardialinfarctions.

Chloroform-Induced Fibrillation in the Mouse

A slightly modified version of the procedure described by Lawson (J.Pharm. Exp. Ther. 160:22-31, 1968) is used.

Methods

Groups of five female Swiss Webster mice, 18 to 23 gm. were given i.p.injections of saline (0.1 ml/10 gm body wt.) or the amidinourea (atequivalent volumes). The amidinourea was administered at doses of 50,25, 12.5, 6.25 and 3.125 mg/kg body wt. Saline was administered to twocontrol groups. After 10 minutes, each mouse was placed in a 1000 ml.beaker containing a gauze pad saturated with 20-30 ml. of chloroform.Each mouse was removed from the beaker immediately after respiratoryarrest and the thoracic cavity opened for visual determination ofventricular activity. Each mouse was scored for the presence ofventricular rhythm or ventricular fibrillation for 15-20 sec. Ifventricular fibrillation was observed, the heart was stroked lightlywith a forceps in an effort to induce ventricular rhythm. Maintenance ofat least five consecutive ventricular beats following cardiac strokingwas scored as ventricular rhythm despite the initial observation offibrillation.

The results of these studies indicate that the amidinourea of thisinvention are useful in maintaining sustained ventricular rhythm despitethe presence of conditions for ventricular fibrillation.

Other tests used to determine the effectiveness of the compounds of thisinvention as anti-arrhythmic agents included:

Ventricular arrhythmias after coronary artery ligation. One-stepligation. Fifteen mongrel dogs of either sex, weight 11 to 15 kg. wereanesthetized with pentobarbital sodium, 30 mg/kg i.v. A tracheostomy wasperformed and the animals were ventilated under positive pressure at aminute volume determined from a body weight nomogram. Blood pressure wasmeasured from the femoral artery via a Statham pressure transducer. Athoracotomy was performed in the left 4th intercostal space and theheart was exposed. The left atrial appendage was reflected and aligature was passed under the left anterior descending coronary arterynear its origin distal to the first major septal perforator. The freeends of the ligature were passed through a short section of polyethylenetubing. The artery could then be occluded by pressing the tubing ontothe vessel while pulling up on the free ends of the ligature. Theocclusion was maintained for 20 minutes by clamping the ligature withKelly forceps. If the animal survived, the occlusion was released andblood flow restored by releasing the clamp and pulling the tubing awayfrom the vessel. The lead II electrocardiogram was monitoredcontinuously on an oscilloscope and continuous recordings were made on aBeckman oscillograph.

Anesthetized, Ouabain-Intoxicated Dog

Ventricular tachycardia and/or multifocal ventricular ectopic rhythmsinduced by intoxication with ouabain in anesthetized dogs have been usedas a classical method for evaluation of anti-arrhythmic activity. Wehave employed this procedure for initial evaluation of anti-arrhythmicactivity of compounds in the amidinourea series, and in recent studieshave attempted to determine their relative effectiveness using severalmodifications of the basic method.

Methods

Male mongrel dogs weighing 8-12 kg. were anesthetized with pentobarbitalsodium, 30 mg/kg i.v. Arterial blood pressure was measured with aStatham transducer and a Beckman Dynagraph recording system via afemoral arterial catheter. The femoral vein was cannulated foradministration of ouabain or the test compounds. Standard Lead IIelectrocardiograms were monitored and used to drive a BeckmanCardiotachometer.

Ouabain (Strophanthin G, obtained from Schwarz/Mann) was initiallyadministered at 40 μgm/kg i.v. with additional injections of 10 μgm/kgi.v. at 15 minute intervals until sustained ventricular tachycardia ormultifocal ventricular ectopic beats were observed. Such arrhythmias aregenerally maintained, but in our studies anti-arrhythmic activity wasmonitored for a maximum of 60 minutes, since spontaneous conversions tonormal sinus rhythm may occur after this period of time.

Three different procedures have been used to determine the effectivelocal anesthetic properties of the compounds of this invention. Thesetests have been used extensively in the past and have been proven toprovide satisfactory results in establishing local anesthetic propertiesof compounds and provide sufficient results to enable one to use thesame.

A discussion of these experimental methods which would enable theskilled artisan to carry out this invention in the manner he sees fitwill be found in Evaluation of Drug Activities: Pharmacometrics, Vol. 1,Ed by D. R. Lawrence and A. L. Bacharach, Academic Press, Inc. (London)Ltd. (1964). Applicants herewith incorporate by reference Chapter 9 ofthis book entitled, "Local Anesthetics", pages 205-214.

The following are detailed examples which show the properties of thecompounds of this invention. They are to be construed as illustrationsof said compounds and not as limitations thereof.

EXAMPLE 1 1-(2',6'-Dimethylphenyl)-3-methylamidinourea hydrochloride

A. 2,6-Dimethylaniline [250 g. (2.06 moles)] is dissolved in 2.5 l. oftoluene at room temperature. The mixture is stirred mechanically whileliquid phosgene [300 ml. (4.2 moles)] is distilled in through a tubeintroduced below the surface of the toluene. When addition of thephosgene is complete, the mixture is heated to reflux for two hoursafter which time, the reaction is essentially complete.

The first 500 ml. of distillate (containing most of the phosgene excess)is now allowed to distil over, and the remainder of the toluene isremoved by vacuum distillation.

The residual crude isocyanate is distilled under vacuo to give2,6-dimethylphenylisocyanate as a clear colorless liquid having a b.p.58° at 1 mm.

B. Methylguanidine sulfate [665 g. (2.72 moles)] sodium hydroxidesolution (50% w/w, 435 g.) and tetrahydrofuran (1250 ml.) are combinedwith vigorous stirring for 2 hours, after which time, with continuedstirring, a solution of 2,6-dimethylphenylisocyanate [400 g. (2.72 moles= 2 equivalents)] in tetrahydrofuran 1 l. is added dropwise.

After addition is complete, (7 hours) the mixture is stirred overnight(14 hours) then concentrated to dryness in vacuo. The residue is dilutedwith water (3500 ml.) and basified to pH 12 with concentrated sodiumhydroxide solution. (200 ml.). Ether (300 ml.) is added and after 45minutes the white solid thus obtained is filtered and washed thoroughlywith water, then with ether (1 l.) Enough methanol is added to dissolvethe precipitate (approximately 4 l.). The methanol solution is driedwith anhydrous sodium sulfate then filtered.

The clear filtered solution is acidified to pH 4 or less by addition ofmethanol saturated with hydrogen chloride, then the mixture isevaporated to dryness. The residual solid is ground and triturated withether, filtered, and washed with ether. The product is dried in vacuo at80° C. for 2 hours to give 1-(2',6'-dimethylphenyl)-3-methylamidinoureahydrochloride (m.p. 194°-197°).

EXAMPLE 2

When methylguanidine sulfate in Example 1 is replaced by the guanidinessulfate of the compounds of Table I below, then the correspondingproduct of Table II below is prepared.

TABLE I

ethylguanidine sulfate

propylguanidine sulfate

i-propylguanidine sulfate

butylguanidine sulfate

i-butylguanidine sulfate

sec-butylguanidine sulfate

t-butylguanidine sulfate

pentylguanidine sulfate

hexylguanidine sulfate

heptylguanidine sulfate

octylguanidine sulfate

nonylguanidine sulfate

decylguanidine sulfate

allylguanidine sulfate

1-(3-butenyl)guanidine sulfate,

1-(2-pentenyl)guanidine sulfate

1-(4-hexenyl)guanidine sulfate

1-(5-heptenyl)guanidine sulfate

propargylguanidine sulfate

1-(2-butynyl)guanidine sulfate

1-(3-heptynyl)guanidine sulfate

cyclopropylguanidine sulfate

cyclobutylguanidine sulfate

cyclopentylguanidine sulfate

cyclohexylguanidine sulfate

cycloheptylguanidine sulfate

1-(2-cyclopentenyl)guanidine sulfate

1-(3-cyclopentenyl)guanidine sulfate

1-(2-cyclohexenyl)guanidine sulfate

1-(3-cyclohexenyl)guanidine sulfate

1-(2-cycloheptenyl)guanidine sulfate

1-(3-cycloheptenyl)guanidine sulfate

1-(4-cycloheptenyl)guanidine sulfate

cyclopropylmethylguanidine sulfate

cyclopropylethylguanidine sulfate

cyclobutylmethylguanidine sulfate

cyclobutylethylguanidine sulfate

cyclopentylethylguanidine sulfate

cyclohexylpropylguanidine sulfate

benzyloxyethylguanidine sulfate

phenethoxyethylguanidine sulfate

benzyloxypropylguanidine sulfate

phenethoxypropylguanidine sulfate

methoxyethylguanidine sulfate

ethoxyethylguanidine sulfate

benzylguanidine sulfate

phenethylguanidine sulfate

1,1-dimethylguanidine sulfate

1,2-dimethylguanidine sulfate

1,1,2-trimethylguanidine sulfate

1,1,-diethylguanidine sulfate

1,2-diethylguanidine sulfate

1,1,2-triethylguanidine sulfate

1-ethyl-1-methylguanidine sulfate

1-ethyl-2-methylguanidine sulfate

1,1-dimethyl-2-ethylguanidine sulfate

1,1-diethyl-2-methylguanidine sulfate

1-methyl-1-propylguanidine sulfate

1-methyl-2-propylguanidine sulfate

1-methyl-1-butylguanidine sulfate

1-methyl-2-butylguanidine sulfate

1,1-dimethyl-2-propylguanidine sulfate

1,1-dimethyl-1-butylguanidine sulfate

1,1-dipropylguanidine sulfate

1,2-dipropylguanidine sulfate

1-ethyl-1-propylguanidine sulfate

1-ethyl-2-propylguanidine sulfate

1-methyl-2-pentylguanidine sulfate

1-methyl-2-hexylguanidine sulfate

1-methyl-2-heptylguanidine sulfate

1-methyl-2-allylguanidine sulfate

1-methyl-2-propargylguanidine sulfate

1-methyl-2-cyclopropylguanidine sulfate

1-methyl-2-(2'-cyclopentenyl)guanidine sulfate

1-methyl-2-cyclopropylmethylguanidine sulfate

1-methyl-2-benzyloxyethylguanidine sulfate

1-methyl-2-phenethoxyethylguanidine sulfate

1-methyl-2-benzyloxypropylguanidine sulfate

1-methyl-2-phenethoxypropylguanidine sulfate

1-methyl-1-benzyloxypropylguanidine sulfate

1-methyl-1-phenethoxyethylguanidine sulfate1-methyl-1-benzyloxyethylguanidine sulfate

1,2-dimethyl-2-benzyloxyethylguanidine sulfate

1-methyl-2-benzylguanidine sulfate

1-methyl-2-phenethylguanidine sulfate

1-ethyl-2-benzyloxyethylguanidine sulfate

1-propyl-2-benzyloxyethylguanidine sulfate

1,1-tetramethyleneguanidine sulfate

1,1-pentamethyleneguanidine sulfate

1,1-hexamethyleneguanidine sulfate

1,1-(3'-oxapentamethylene)guanidine sulfate

1,1-(N-methyl-3'-azapentamethylene)guanidine sulfate

1,1-(N-methyl-3'-azahexamethylene)guanidine sulfate

1,1,2,2-tetramethylguanidine sulfate

1,1-dimethyl-2,2-diethylguanidine sulfate

1,2-dimethyl-1,2-diethylguanidine sulfate

1,1,2-trimethyl-2-ethylguanidine sulfate

1,1,2,2-tetraethylguanidine sulfate

1,1,2,2-tetrapropylguanidine sulfate

1,1,2,2-tetrabutylguanidine sulfate

1-methyl-2-ethyl-1,2-dipropylguanidine sulfate

1,1-pentamethylene-2-methylguanidine sulfate

1,1-pentamethylene-2,2-pentamethyleneguanidine sulfate

1,1-tetramethylene-2-methylguanidine sulfate

1,1-pentamethylene-2,2-dimethylguanidine sulfate

1,1-pentamethylene-2,2-tetramethyleneguanidine sulfate

1,1-pentamethylene-2-methyl-2-ethylguanidine sulfate

1,1-tetramethylene-2-allylguanidine sulfate

1,1-tetramethylene-2-benzyloxyethylguanidine sulfate

1,1-tetramethylene-2-propargylguanidine sulfate

1-methyl-1-propargyl-2-ethyl-2-pentylguanidine sulfate

1,1-hexamethylene-2-methylguanidine sulfate

1,1-hexamethylene-2,2-dimethylguanidine sulfate

1,1-(3'-oxapentamethylene)-2-methylguanidine sulfate

1,1-(N-methyl-3'-azahexamethylene)-2,2-dimethylguanidine sulfate

1,1-(N-methyl-3'-azahexamethylene)-2,2-tetramethyleneguanidine sulfate

1-(3'-butynyl)guanidine sulfate

1-(2-butenyl)guanidine sulfate

1-methyl-1-allylguanidine sulfate

1-methyl-1-propargylguanidine sulfate

1-methyl-1-cyclopropylmethylguanidine sulfate

1-methyl-1-methoxyethylguanidine sulfate

1-methyl-1-benzyloxyethylguanidine sulfate

1,1-tetramethylene-2-ethylguanidine sulfate

1,1-tetramethylene-2,2-tetramethylene

1,1-(2'-thiapentamethylene)guanidine sulfate

1,1-(2'-thiatetramethylene)guanidine sulfate

TABLE II

1-(2',6'-dimethylphenyl)-3-ethylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-propylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-i-propylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-butylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-i-butylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-sec-butylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-t-butylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-pentylamidinourea hydrochloride

1-(2',5'-dimethylphenyl)-3-hexylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-heptylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-octylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-nonylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-decylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-allylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-[N-(3'-butenyl)amidino]urea hydrochloride

1-(2',6'-dimethylphenyl)-3-[N-(2'-pentenyl)amidino]urea hydrochloride

1-(2',6'-dimethylphenyl)-3-[N-(4'-hexenyl)amidino]urea hydrochloride

1-(2',6'-dimethylphenyl)-3-[N-(5'-heptenyl)amidino]urea hydrochloride

1-(2',6'-dimethylphenyl)-3-propargylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N-allyl-N-methylamidino) urea hydrochloride

1-(2',6'-dimethylphenyl)-3-[N-(3'-heptynyl)amidino]urea hydrochloride

1-(2',6'-dimethylphenyl)-3-cyclopropylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-cyclobutylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-cyclopentylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-cyclohexylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-cycloheptylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-[N-(2'-cyclopentenyl)amidino]ureahydrochloride

1-(2',6'-dimethylphenyl)-3-[N-(3'-cyclopentenyl)amidino]ureahydrochloride1-(2',6'-dimethylphenyl)-3-[N-(2'-cyclohexenyl)amidino]ureahydrochloride

1-(2',6'-dimethylphenyl)-3-[N-(3'-cyclohexenyl)amidino]ureahydrochloride

1-(2',6'-dimethylphenyl)-3-[N-(2'-cycloheptenyl)amidino]ureahydrochloride

1-(2',6'-dimethylphenyl)-3-[N-(3'-cycloheptenyl)amidino]ureahydrochloride

1-(2',6'-dimethylphenyl)-3-[N-(4'-cycloheptenyl)amidino]ureahydrochloride

1-(2',6'-dimethylphenyl)-3-cyclopropylmethylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-cyclopropylethylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-cyclobutylmethylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-cyclobutylethylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-cyclopentylethylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-cyclohexylpropylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-benzyloxyethylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-phenethoxyethylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-methoxyethylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-ethoxyetnylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-benzylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-phenethylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-dimethylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N'-dimethylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N,N'-trimethylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-diethylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N'-diethylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N,N'-triethylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N-ethyl-N-methylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N-ethyl-N'-methylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-dimethyl-N'-ethylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-diethyl-N'-methylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-propylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N'-propylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-butylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N'-butylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-dimethyl-N'-propylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-dimethyl-N-butylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-dipropylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-dipropylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N'-dipropylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N-ethyl-N-propylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N'-ethyl-N-propylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N'-methyl-N-pentylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N'-methyl-N-hexylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N'-methyl-N-heptylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N'-methyl-N-allylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N'-methyl-N-propargylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N'-methyl-N-cyclopropylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N'-methyl-N-(2-cyclopentenyl)amidino]ureaHCl

1-(2',6'-dimethylphenyl)-3-(N'-methyl-N-cyclopropylmethylamidino)ureaHCl

1-(2',6'-dimethylphenyl)-3-(N'-methyl-N-benzyloxyethylamidino)urea HCl

1-(2',6'-dimethylphenyl)-3-(N'-methyl-N-phenethoxyethylamidino)urea HCl

1-(2',6'-dimethylphenyl)-3-(N'-methyl-N-benzyloxypropylamidino)urea HCl

1-(2',6'-dimethylphenyl)-3-(N'-methyl-N-phenethoxypropylamidino)urea HCl

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-benzyloxypropylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-phenethoxyethylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-benzyloxyethylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N'-dimethyl-N-benzyloxyethylamidino)ureaHCl

1-(2',6'-dimethylphenyl)-3-(N'-methyl-N-benzylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N'-methyl-N-phenethylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N'-ethyl-N-bezyloxyethylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N'-propyl-N-benzyloxyethylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-tetramethyleneamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-pentamethyleneamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-hexamethyleneamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-[N,N-(3'-oxapentamethylene)amidino]ureahydrochloride

1-(2',6'-dimethylphenyl)-3-[N,N-(3'-methyl-3'-azapentamethylene)amidino]ureaHCl

1-(2',6'-dimethylphenyl)-3-[N,N-(3'-methyl-3'-azahexamethylene)amidino]urea HCl

1-(2',6'-dimethylphenyl)-3-[N,N-(3'-thiapentamethylene)amidino]ureahydrochloride

1-(2',6'-dimethylphenyl)-3-[N,N-(2'-thiatetramethylene)amidino]ureahydrochloride

1-(2',6'-dimethylphenyl)-3-[N-(2'-butenyl)amidino]urea hydrochloride

1-(2',6'-dimethylphenyl)-3-[N-(2'-butynyl)amidino]urea hydrochloride

1-(2',6'-dimethylphenyl)-3-[N-(3'-butynyl)amidino]urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-allylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-propargylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-cyclopropylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N,N',N'-tetramethylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-dimethyl-N',N'-diethylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N'-dimethyl-N,N'-diethylamidino)ureahydrochloride

1(2',6'-dimethylphenyl)-3-(N,N,N'-trimethyl-N'-ethylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N,N',N'-tetraethylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N,N',N'-tetrapropylamidino)ureahydrochloride

1-(2',6'dimethylphenyl)-3-(N,N,N',N'-tetrabutylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N'-ethyl-N,N'-dipropylamindino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-pentamethylene-N'-methylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-pentamethylene-N',N'-pentamethyleneamidino)ureahydrochloride

1-(2',6'L-dimethylphenyl)-3-(N,N-tetramethylene-N'-methylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-pentamethylene-N',N'-dimethylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-pentamethylene-N',N'-tetramethyleneamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-pentamethylene-N'-methyl-N'-ethylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-tetrametylene-N'-allylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-tetramethylene-N'-benzyloxyethylamidino)ureahydrochloride

1(2',6'-dimethylphenyl)-3-(N,N-tetramethylene-N'-propargylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-propargyl-N'-pentylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-hexamethylene-N'-methylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-hexamethylene-N',N'-dimethylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)3-[N,N-(3'-oxapentamethylene)-N'-methylamidino]ureahydrochloride

1-(2',6'-dimethylphenyl)-3-[N,N-(3-methyl-3'-azahexamethylene)-N',N'-dimethylamidino]ureahydrochloride

1-(2',6'-dimethylphenyl)-3-[N,N-(3'-methyl-3'-azahexamethylene)-N',N'-tetramethyleneamidino]ureahydrochloride

EXAMPLE 3

When methylguanidine sulfate in Example 1 is replaced by

methylguanidine hydrochloride

methylguanidine hydrobromide

methylguanidine carbonate or

methylguanidine nitrate

then the same product is prepared.

When the guanidines of Table I, Example 2, are used in the procedure ofExample 1 as a salt other than the sulfate, then the same product isobtained.

EXAMPLE 4

When methylguanidine sulfate in Example 1 is replaced by methylguanidineand the sodium hydroxide solution is eliminated from the reactionprocedure, then the same product is prepared.

When the free base of the guanidines is used in Examples 2 and 3 and thesodium hydroxide solution is eliminated from the reaction procedure,then the same product is prepared.

EXAMPLE 5

When it is desired to obtain the free base of the resultant amidinoureaby the procedures of Examples 1-4, then the final step for preparing thehydrochloride salt is eliminated.

When it is desired to obtain the resultant amidinourea in the form of asalt other than the hydrochloride then the corresponding acid would beused in the final step of the reaction in place of the hydrogenchloride.

EXAMPLE 6

When the procedure of Example 1 is followed and the anilines of Table Ibelow are used with the various guanidines of Examples 1-4, then thecorresponding substituted amidinoureas ae prepared. A representativelist of the compounds so prepared is shown in Table II below.

TABLE I

2,3-dimethylaniline

2,4-dimethylaniline

2,5-dimethylaniline

3,4-dimethylaniline

3,5-dimethylaniline

2,3-diethylaniline

2,4-diethylaniline

2,5-diethylaniline

2,6-diethylaniline

3,4-diethylaniline

3,5-diethylaniline

2-methyl-4-ethylaniline

2-ethyl-4-methylaniline

2-methyl-6-ethylaniline

2-methyl-3-ethylaniline

2,6-diisopropylaniline

2-methyl-5-ethylaniline

3-methyl-4-ethylaniline

3-methyl-5-ethylaniline

2-ethyl-3-methylaniline

2-methyl-6-isopropylaniline

2-ethyl-5-methylaniline

3-ethyl-4-methylaniline

2-methyl-6-propylaniline

2-ethyl-6-propylaniline

2,6-dipropylaniline

2-methyl-6-i-propylaniline

2-methyl-6-butylaniline

2-ethyl-6-butylaniline

2-methyl-6-chloroaniline

2-methyl-6-fluoroaniline

2-methyl-6-bromoaniline

2-methyl-6-iodoaniline

2-methyl-6-methoxyaniline

2-methyl-6-ethoxyaniline

2-methyl-6-trifluoromethylaniline

2-methyl-6-nitroaniline

2-ethyl-6-chloroaniline

2-ethyl-6-fluoroaniline

2-ethyl-6-bromoaniline

2-ethyl-6-methoxyaniline

2-ethyl-6-ethoxyaniline

2-ethyl-6-trifluoromethylaniline

2-propyl-6-chloroaniline

2-propyl-6-fluoroaniline

2-propyl-6-bromoaniline

2-propyl-6-methoxyaniline

2-propyl-6-ethoxyaniline

2-i-propyl-6-chloroaniline

2-i-propyl-6-fluoroaniline

2-i-propyl-6-methoxyaniline

2-butyl-6-chloroaniline

2-methyl-3-chloroaniline

2-methyl-4-chloroaniline

2-methyl-5-chloroaniline

2,3-dichloroaniline

2,4-dichloroaniline

2,5-dichloroaniline

2,6-dichloroaniline

3,4-dichloroaniline

3,5-dichloroaniline

2-chloro-6-bromoaniline

2-chloro-3-methylaniline

2-chloro-4-methylaniline

2-chloro-5-methylaniline

2-chloro-5-fluoroaniline

2-chloro-5-bromoaniline

2-chloro-5-trifluoromethylaniline

2-fluoro-5-chloroaniline

2-chloro-6-fluoroaniline

2-bromo-6-fluoroaniline

2,6-difluoroaniline

2-methylaniline

2-ethylaniline

2-propylaniline

4-trifluoromethylaniline

3,4-dimethoxyaniline

3,4,5-trimethoxyaniline

2-trifluoromethylaniline

2-methyl-4-bromoaniline

2-methyl-4-fluoroaniline

2-ethyl-4-chloroaniline

2-ethyl-4-fluoroaniline

2-methyl-4-methoxyaniline

2-ethyl-4-methoxyaniline

2,4,6-trimethylaniline

2,4,6-triethylaniline

2,4-diethyl-6-methylaniline

2,6-diethyl-4-methylaniline

2-methyl-4-propyl-6-ethylaniline

2,4-dimethyl-6-ethylaniline

2,4-dimethyl-6-chloroaniline

2,4-dimethyl-6-bromoaniline

2,4-dimethyl-6-fluoroaniline

2,4-dimethyl-6-trifluoromethylaniline

2,4-dimethyl-6-nitroaniline

2,4-dimethyl-6-methoxyaniline

2,6-dimethyl-4-ethylaniline

2,6-dimethyl-4-chloroaniline

2,6-dimethyl-4-bromoaniline

2,6-dimethyl-4-fluoroaniline

2,6-dimethyl-4-nitroaniline

2,6-dimethyl-4-methoxyaniline

2,6-dimethyl-4-propylaniline

2-methyl-4,6-dichloroaniline

2-methyl-4,6-difluoroaniline

2-methyl-4-fluoro-6-bromoaniline

2-methyl-4-fluoro-6-chloroaniline

2-methyl-4-bromo-6-chloroaniline

2-methyl-4-chloro-6-fluoroaniline

2-methyl-4-chloro-6-bromoaniline

2-methyl-4-methoxy-6-chloroaniline

2-methyl-4-ethyl-6-chloroaniline

2-methyl-4-chloro-6-trifluoromethylaniline

2-methyl-4-trifluoromethyl-6-chloroaniline

2-ethyl-4,6-dichloroaniline

2-ethyl-4,6-difluoroaniline

2-ethyl-4-fluoro-6-bromoaniline

2-ethyl-4-fluoro-6-chloroaniline

2-ethyl-4-bromo-6-chloroaniline

2-ethyl-4-chloro-6-fluoroaniline

2-ethyl-4-chloro-6-bromoaniline

2,6-diethyl-4-chloroaniline

2,6-diethyl-4-bromoaniline

2,6-diethyl-4-fluoroaniline

2-nitroaniline

4-nitroaniline

2,6-dibromoaniline

2,6-diiodoaniline

2-methyl-6-iiodoaniline

4-hydroxy-2,6-dimethylaniline

4-hydroxy-2,6-diethylaniline

4-hydroxy-2-methylaniline

4-hydroxy-2-methyl-6-ethylaniline

4-benzyloxy-2,6-dimethylaniline

4-benzyloxy-2,6-diethylaniline

4-amino-2,6-diethylaniline

3-nitro-2,6-dimethylaniline

4-amino-2,6-dimethylaniline

3-bromo-2,6-dimethylaniline

3-cyano-2,6-dimethylaniline

4-amino-2-i-propylaniline

4-acetylamino-2-i-propylaniline

4-acetylamino-2,6-dimethylaniline

4-acetylamino-2,6-diethylaniline

2-isopropyl-4-acetylamino-6-ethylaniline

2-methyl-6-chloro-4-hydroxy

2-methyl-6-bromo-4-hydroxy

2-methyl-6-fluoro-4-hydroxy

2-ethyl-6-chloro-4-hydroxy

2-ethyl-6-bromo-4-hydroxy

2-ethyl-6-fluoro-4-hydroxy

2-methyl-6-chloro-4-amino

2-methyl-6-bromo-4-amino

2-methyl-6-fluoro-4-amino

2-ethyl-6-chloro-4-amino

2-ethyl-6-bromo-4-amino

2-ethyl-6-fluoro-4-fluoro-4-amino

2-methyl-6-chloro-4-acetylaminoanaline

2-methyl-6-bromo-4-acetylaminoanaline

2-methyl-6-fluoro-4-acetylaminoanaline

2-ethyl-6-chloro-4-acetylaminoanaline

2-ethyl-6-bromo-4-acetylaminoanaline

2-ethyl-6-fluoro-4-acetylaminoanaline

EXAMPLE 7 1-(2',6'-Dimethylphenyl)-1-methyl-3-methylamidinourea nitrate

A. 125 g. of 2,6 dimethyl aniline and 375 ml. of 88% formic acid aremixed in a 1 liter bomb with magnetic stirrer. The temperature (oilbath) is brought to 120° C. The bomb is kept at this temperature for 24hours. The bomb is then allowed to cool to room temperature and stirringcontinued for 48 hours. The pressure is released and the mixture ispoured into an 800 ml. ice with stirring. The mixture is filtered andthe solid washed extensively with water and sucked dry and then dried invacuo at 90°-95° to give N-formyl-2,6-dimethylaniline (m.p. 163°-164.5°C.).

B. A suspension of 125.6 g. of 2,6-dimethylformanilide in 1100 ml. ofdry tetrahydrofuran is cooled to 0° C. in ice-methanol. To this withconstant stirring is added dropwise over a period of 3 hours 1125 ml. of0.96 M BH₃ in tetrahydrofuran. This is then allowed to warm gradually toroom temperature and then heated slowly to reflux. Refluxing ismaintained for 6 hours and then stirred at room temperature another 15hours. The reaction mixture is then cooled in ice and acidified with 425ml. of 6 N HCl. A white solid forms. The mixture is evaporated in vacuoand the water-solid slurry dissolved into 2 l. of water. The solution ismade strongly alkaline (with cooling) with 50% NaOH and then extractedtwice with ether (2 l.) The ether is then washed three times with 100ml. portions of water and twice with 100 ml. portions of saturatedsodium chloride solution. The ether is then dried over sodium sulfate,filtered, acidified with ethereal HCl while cooling. The white solidwhich forms is filtered, washed with ether and sucked dry. This isrecrystallized from isopropanol:methanol to give N,2,6-trimethylanilinehydrochloride (m.p. 255-257 dec.)

C. Into a suspension of 121.1 g. (0.71 moles) of N,2,6-trimethylanilinehydrochloride in 1 l. of benzene at reflux is bubbled an excess ofphosgene (0.175 ml. of liquid or 1.6 moles). After introduction of thephosgene, the mixture is refluxed for 1 hour and then 700 ml. of benzeneremoved by distillation at slightly reduced pressure. After the phosgeneis gone the residue is triturated with hexane (300 ml.), filtered anddried to give 2,6-dimethylphenyl-N-methylcarbamoyl chloride (m.p.79°-80° C.).

D. To a suspension of 12.21 g. (0.05 moles) of methyl guanidine sulfatein 110 ml. of tetrahydrofuran is added 8.0 g. (0.10 moles of sodiumhydroxide) of 50% aqueous sodium hydroxide. After stirring for 11/2hours, 4.5 g. of sodium sulfate is slowly added and the mixture stirredan additional 1/2 hour. To the solution is added a solution of 9.88 g.(0.05 moles) of 2,6-dimethylphenyl-N-methylcarbamoyl chloride in 30 ml.of tetrahydrofuran. After stirring for 24 hours, the THF is removed invacuo and the residue partitioned with chloroform/water. The oilyresidue is triturated with 300 ml. of hexane and 20 ml. benzene to givea white solid. This is dissolved in 50 ml. of 1:4 HNO₃ and warmedslightly over 1/2 hour, then cooled. The white solid which forms isfiltered and air dried to obtain1-(2',6'-dimethylphenyl)-1-methyl-3-methylamidinourea nitrate.

When formic acid in the above procedure is replaced by acetic acid,propionic acid, butyric acid or pentanoic acid then the productsprepared are:

1-(2',6'-dimethylphenyl)-1-ethyl-3-methylamidinourea

1-(2'-6'-dimethylphenyl)-1-propyl-3-methylamidinourea

1-(2',6'-dimethylphenyl)-1-butyl-3-methylamidinourea

1-(2',6'-dimethylphenyl)-1-pentyl-3-methylamidinourea

When methyl guanidine sulfate in the above procedure is replaced by theguanidines of Examples 2-4 then the corresponding amidinourea isprepared. A representative list of the compounds so prepared is shown inTable I below.

TABLE I

1-(2',6'-dimethylphenyl)-1-methyl-3-ethylamidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-propylamidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-i-propylamidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-butylamidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-allylamidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-propargylamidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-cyclopropylamidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-cyclobutylamidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-(3-cyclohexenylamidino)urea

1-(2',6'-dimethylphenyl)-1-methyl-3-cyclopropylmethylamidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-benzyloxyethylamidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-benzyloxypropylamidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-phenoxyethylamidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-benzylamidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N,N-dimethylamidino)urea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N,N'-dimethylamidino)urea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N,N,N'-trimethylamidino)urea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N,N-diethylamidino)urea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N-ethyl-N-methylamidino)urea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N-ethyl-N'-methylamidino)urea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N'-methyl-N-benzyloxyethylamidino)urea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N'-methyl-N-allylamidino)urea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N,N-pentamethyleneamidino)urea

1-(2',6'-dimethylphenyl)-1-ethyl-3-ethylamidinourea

1-(2',6'-dimethylphenyl)-1-ethyl-3-propylamidinourea

1-(2',6'-dimethylphenyl)-1-ethyl-3-i-propylamidinourea

1-(2',6'-dimethylphenyl)-1-ethyl-3-butylamidinourea

1-(2',6'-dimethylphenyl)-1-ethyl-3-t-butylamidinourea

1-(2',6'-dimethylphenyl)-1-ethyl-3-allylamidinourea

1-(2',6'-dimethylphenyl)-1-ethyl-3-propargylamidinourea

1-(2',6'-dimethylphenyl)-1-ethyl-3-cyclopropylamidinourea

1-(2',6'-dimethylphenyl)-1-ethyl-3-cyclohexylamidinourea

1-(2',6'-dimethylphenyl)-1-ethyl-3-[N-(3'-cyclopentenyl)amidino]urea

1-(2',6'-dimethylphenyl)-1-ethyl-3-cyclopropylmethylamidinourea

1-(2',6'-dimethylphenyl)-1-ethyl-3-cyclopropylethylamidinourea

1-(2',6'-dimethylphenyl)-1-ethyl-3-benzyloxyethylamidinourea

1-(2',6'-dimethylphenyl)-1-ethyl-3-benzyloxypropylamidinourea

1-(2',6'-dimethylphenyl)-1-ethyl-3-phenethoxymethylamidinourea

1-(2',6'-dimethylphenyl)-1-ethyl-3-phenethoxyethylamidinourea

1-(2',6'-dimethylphenyl)-1-ethyl-3-benzylamidinourea

1-(2',6'-dimethylphenyl)-1-ethyl-3-(N,N-dimethylamidino)urea

1-(2',6'-dimethylphenyl)-1-ethyl-3-(N,N'-dimethylamidino)urea

1-(2',6'-dimethylphenyl)-1-ethyl-3-(N,N,N'-trimethylamidino)urea

1-(2',6'-dimethylphenyl)-1-ethyl-3-(N,N-diethylamidino)urea

1-(2',6'-dimethylphenyl)-1-ethyl-3-(N,N,N'-triethylamidino)urea

1-(2',6'-dimethylphenyl)-1-ethyl-3-(N-ethyl-N-methylamidino)urea

1-(2',6'-dimethylphenyl)-1-ethyl-3-(N-ethyl-N'-methylamidino)urea

1-(2',6'-dimethylphenyl)-1-ethyl-3-(N-ethyl-N-propylamidino)urea

1-(2',6'-dimethylphenyl)-1-ethyl-3-(N-ethyl-N-allylamidino)urea

1-(2',6'-dimethylphenyl)-1-ethyl-3-(N-methyl-N-propargylamidino)urea

1-(2',6'-dimethylphenyl)-1-ethyl-3-(N-methyl-N-benzyloxyethylamidino)urea

1-(2',6'-dimethylphenyl)-1-ethyl-3-(N,N-tetramethyleneamidino)urea

1-(2',6'-dimethylphenyl)-1-ethyl-3-[N,N-(3'-oxapentamethylene)amidino]urea

1-(2',6'-dimethyl)-1-propyl-3-methylamidinourea

1-(2',6'-dimethylphenyl)-1-propyl-3-ethylamidinourea

1-(2',6'-dimethylphenyl)-1-propyl-3-propylamidinourea

1-(2',6'-dimethylphenyl)-1-propyl-3-allylamidinourea

1-(2',6'-dimethylphenyl)-1-propyl-3-propargylamidinourea

1-(2',6'-dimethylphenyl)-1-propyl-3-benzyloxyethylamidinourea

1-(2',6'-dimethylphenyl)-1-propyl-3-(N,N-dimethylamidino)urea

1-(2',6'-dimethylphenyl)-1-butyl-3-methylamidinourea

1-(2',6'-dimethylphenyl)-1-butyl-3-ethylamidinourea

1-(2',6'-dimethylphenyl)-1-pentyl-3-methylamidinourea

1-(2',6'-dimethylphenyl)-1-pentyl-3-ethylamidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-i-butylamidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-(2-butynyl)amidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-cyclopentyl amidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-cyclohexyl amidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-pentyl amidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-hexyl amidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-butenyl amidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-pentenyl amidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-hexenyl amidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N,N-dimethyl-N'-ethylamidino)urea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N,N-diethyl-N'-methylamidino)urea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N-ethyl-N-methyl-N'-methylamidino)urea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N,N-pentamethylene-N'-methylamidino)urea

1-(2',6'-dimethylphenyl)-1-ethyl-3-i-butylamidinourea

1-(2',6'-dimethylphenyl)-1-butyl-3-i-butylamidinourea

1-(2',6'-dimethylphenyl)-1-pentyl-3-i-butyl amidinourea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N,N-dimethylamidino)urea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N,N'-dimethylamidino)urea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N,N,N'-trimethylamidino)urea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N,N,N',N'-tetramethylamidino)urea

1-(2',6'-dimethylphenyl)-1-methyl-3-(N,N-pentamethylene-N,N-pentamethyleneamidino)urea

When 2,6-dimethylaniline in the above procedure is replaced by theanilines of example 6, then the corresponding product is obtained.

When the above procedure is followed using the anilines of Example 6 andthe guanidines of Examples 2-4, then the corresponding product isobtained. A representative list of products so prepared are shown inTable II below.

TABLE II

1-(2',6'-diethylphenyl)-3-methylamidinourea

1-(2',6'-diethylphenyl)-1-methyl-3-methylamidinourea

1-(2',6'-diethylphenyl)-1-methyl-3-(N,N-dimethylamidino)urea

1-(2',6'-diethylphenyl)-1-methyl-3-(N,N'-dimethylamidino)urea

1-(2',6'-diethylphenyl)-1-methyl-3-(N,N,N'-trimethylamidino)urea

1-(2',6'-diethylphenyl)-3-(N,N'-dimethylamidino)urea

1-(2',6'-diethylphenyl)-3-(N,N,N'-trimethylamidino)urea

1-(2',6'-diethylphenyl)-3-(N,N,N',N'-tetramethylamidino)urea

1-(2',6'-diethylphenyl)-1-methyl-3-(N,N,N',N'-tetramethylamidino)urea

1-(2',6'-diethylphenyl)-3-ethylamidinourea

1-(2',6'-diethylphenyl)-3-propylamidinourea

1-(2',6'-diethylphenyl)-3-i-propylamidinourea

1-(2',6'-diethylphenyl)-3-butylamidinourea

1-(2',6'-diethylphenyl)-3-i-butylamidinourea

1-(2',6'-diethylphenyl)-3-pentylamidinourea

1-(2',6'-diethylphenyl)-3-allylamidinourea

1-(2',6'-diethylphenyl)-3-propargylamidinourea

1-(2',6'-diethylphenyl)-3-cyclopropylamidinourea

1-(2',6'-diethylphenyl)-3-methoxyethylamidinourea

1-(2',6'-diethylphenyl)-3-benzyloxyethylamidinourea

1-(2',6'-diethylphenyl)-3-penethoxyethylamidinourea

1-(2',6'-diethylphenyl)-3-benzylamidinourea

1-(2',6'-diethylphenyl)-3-(N,N-dimethylamidino)urea

1-(2',6'-diethylphenyl)-3-(N,N'-dimethylamidino)urea

1-(2',6'-diethylphenyl)-3-(N,N-diethylamidino)urea

1-(2',6'-diethylphenyl)-3-(N,N'-diethylamidino)urea

1-(2',6'-diethylphenyl)-3-(N-ethyl-N'-methylamidino)urea

1-(2',6'-diethylphenyl)-3-(N'-methyl-N-benzyloxyethylamidino)urea

1-(2',6'-diethylphenyl)-3-(N,N-tetramethyleneamidino)urea

1-(2',6'-diethylphenyl)-3-(N,N-pentamethyleneamidino)urea

1-(2',6'-diethylphenyl)-3-(N-methyl-N'-propargylamidino)urea

1-(2',6'-diethylphenyl)-3-(N,N-tetramethylene-N'-allylamidino)urea

1-(2',6'-diethylphenyl)-3-(N,N-tetramethylene,N',N'-tetramethyleneamidino)urea

1-(2',6'-diethylphenyl)-1-methyl-3-ethylamidinourea

1-(2',6'-diethylphenyl)-1-methyl-3-propylamidinourea

1-(2',6'-diethylphenyl)-1-methyl-3-i-propylamidinourea

1-(2',6'-diethylphenyl)-1-methyl-3-butylamidinourea

1-(2',6'-diethylphenyl)-1-methyl-3-i-butylamidinourea

1-(2',6'-diethylphenyl)-1-methyl-3-allylamidinourea

1-(2',6'-diethylphenyl)-1-methyl-3-propargylamidinourea

1-(2',6'-diethylphenyl)-1-methyl-3-methoxyethylamidinourea

1-(2',6'-diethylphenyl)-1-methyl-3-benzyloxyethylamidinourea

1-(2',6'-diethylphenyl)-1-methyl-3-phenoxyethylamidinourea

1-(2',6'-diethylphenyl)-1-methyl-3-(N,N-diethylamidino)urea

1-(2',6'-diethylphenyl)-1-methyl-3-(N'-methyl-N-benzyloxyethylamidino)urea

1-(2',6'-diethylphenyl)-1-methyl-3-(N,N-pentamethyleneamidino)urea

1-(2',6'-diethylphenyl)-1-methyl-3-(N,N,N'-trimethylamidino)urea

1-(2',6'-diethylphenyl)-1-methyl-3-(N,N,N'-triethylamidino)urea

1-(2',6'-diethylphenyl)-1-methyl-3-(N,N,N',N'-tetraethylamidino)urea

1-(2',6'-diethylphenyl)-1-ethyl-3-methylamidinourea

1-(2',6'-diethylphenyl)-1-ethyl-3-methylamidinourea

1-(2',6'-diethylphenyl)-1-ethyl-3-propylamidinourea

1-(2',6'-diethylphenyl)-1-ethyl-3-butylamidinourea

1-(2',6'-diethylphenyl)-1-ethyl-3-i-butylamidinourea

1-(2',6'-diethylphenyl)-1-ethyl-3-(N,N-diethylamidino)urea

1-(2',6'-diethylphenyl)-1-ethyl-3-(N,N'-diethylamidino)urea

1-(2',6'-diethylphenyl)-1-ethyl-3-(N,N,N'-triethylamidino)urea

1-(2',6'-diethylphenyl)-1-ethyl-3-(N,N,N',N',-tetraethylamidino)urea

1-(2',6'-diethylphenyl)-1-ethyl-3-allylamidinourea

1-(2',6'-diethylphenyl)-1-ethyl-3-propargylamidinourea

1-(2',6'-diethylphenyl)-1-ethyl-3-methoxyethylamidinourea

1-(2',6'-diethylphenyl)-1-ethyl-3-benzyloxyethylamidinourea

1-(2',6'-diethylphenyl)-1-ethyl-3-phenethoxyethylamidinourea

1-(2',6'-diethylphenyl)-1-propyl-3-methylamidinourea

1-(2',6'-diethylphenyl)-1-propyl-3-ethylamidinourea

1-(2',6'-diethylphenyl)-1-propyl-3-propylamidinourea

1-(2',6'-diethylphenyl)-1-propyl-3-butylamidinourea

1-(2',6'-diethylphenyl)-1-propyl-3-i-butylamidinourea

1-(2',6'-diethylphenyl)-1-propyl-3-(N,N-dimethylamidino)urea

1-(2',6'-diethylphenyl)-1-propyl-3-(N,N,N'-trimethylamidino)urea

1-(2',6'-diethylphenyl)-1-propyl-3-allylamidinourea

1-(2',6'-diethylphenyl)-1-propyl-3-propargylamidinourea

1-(2',6'-diethylphenyl)-1-propyl-3-methoxyethylamidinourea

1-(2',6'-diethylphenyl)-1-propyl-3-benzyloxyethylamidinourea

1-(2',6'-diethylphenyl)-1-butyl-3-methylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-methylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-ethylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-propylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-i-propylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-butylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-i-butylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-t-butylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-pentylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-allylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-propargylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-cyclopropylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-cyclobutylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-[N-(3'-cyclopentenyl)amidino]urea

1-(2'-methyl-6'-ethylphenyl)-3-cyclopropylmethylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-cyclobutylethylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-methoxyethylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-benzyloxyethylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-phenethoxyethylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-benzylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-(N,N-dimethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-3-(N,N'-dimethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-3-(N,N,N'-trimethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-3-(N,N,N,N'-tetramethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-3-(N,N-diethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-3-(N,N'-diethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-3-(N-methyl-N'-ethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-3-(N-methyl-N'-benzyloxyethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-3-(N,N-tetramethyleneamidino)urea

1-(2'-methyl-6'-ethylphenyl)-3-(N,N-tetramethylene-N',N'-tetramethyleneamidino)urea

1-(2'-methyl-6'-ethylphenyl)-3-[N,N(3'-methyl-3'-azapentamethylene)amidino]urea

1-(2'-methyl-6'-ethylphenyl)-3-[N,N-(3'-oxapentamethylene)amidino]urea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-methylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-ethylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-propylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-i-propylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-butylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-i-butylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-t-butylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-allylamidonourea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-propargylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-methoxyethylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-benzyloxyethylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-phenethoxyethylamidinourea

1-(2'-methyl-6'-ethylphenzl)-1-methyl-3-(N,N-dimethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-(N,N-diethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-(N,N'-dimethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-(N-methyl-N'-ethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-(N-ethyl-N'-benzyloxyethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-(N-ethyl-N'-allylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-(N-ethyl-N'-propargylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-(N,N-tetramethyleneamidino)urea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-(N,N,N'-trimethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-1-methyl-3-(N,N,N,N'-tetramethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-1-ethyl-3-methylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-ethyl-3-ethylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-ethyl-3-propylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-ethyl-3-butylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-ethyl-3-i-butylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-ethyl-3-(N,N-dimethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-1-ethyl-3-(N,N'-dimethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-1-ethyl-3-(N,N-diethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-1-ethyl-3-(N',N,N'-trimethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-1-ethyl-3-allylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-ethyl-3-propargylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-ethyl-3-methoxyethylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-ethyl-3-benzyloxyethylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-ethyl-3-pheneoxyethylamidinourea

1-(2'-methyl-6'-ethylphenyl)-1-ethyl-3-(N-methyl-N'-allylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-1-ethyl-3-(N-ethyl-N'-benzyloxyethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-3-methylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-ethylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-propylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-i-propylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-butylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-i-butylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-t-butylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-pentylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-allylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-propargylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-cyclobutylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-cyclohexylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-benzylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-methoxyethylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-benzyloxyethylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-phenethoxyethylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-(N,N-dimethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-3-(N,N'-dimethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-3-(N,N-diethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-3-(N,N'-diethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-3-(N-ethyl-N'-methylamidino)urea1-(2'-methyl-6'-chlorophenyl)-3-(N-methyl-N'-allylamidino)urea

1-(2"-methyl-6'-chlorophenyl)-3-(N-methyl-N'-propargylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-3-(N-ethyl-N'-benzyloxyethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-3-(N-propyl-N'-allylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-3-(N,N-pentamethyleneamidino)urea

1-(2'-methyl-6'-chlorophenyl)-3-(N,N-tetramethylene-N'-methylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-3-(N,N,N'-trimethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-3-(N,N,N',N'-tetramethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-3-(N,N-tetramethylene-N',N'-tetramethyleneamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-methylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-ethylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-propylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-i-propylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-butylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-i-butylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-t-butylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-pentylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-hexylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-heptylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-allylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-propargylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-methoxyethylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-benzyloxyethylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-phenethoxyethylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-benzylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-(N,N-dimethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-(N,N'-dimethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-(N,N-diethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-(N,N'-diethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-(N-methyl-N'-ethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-(N'-methyl-N-benzyloxyethylamidino)urea1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-(N'-allyl-N-methylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-(N'-propargyl-N-methylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-(N,N-tetramethyleneamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-(N,N,N'-trimethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-methyl-3-(N,N,N',N'-tetramethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-methylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-ethylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-propylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-i-propylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-butylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-i-butylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-t-butylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-methoxyethylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-benzyloxyethylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-allylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-propargylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-(N,N-dimethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-(N,N'-dimethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-(N,N-diethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-(N,N'-diethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-(N,N,N'-trimethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-(N,N,N',N'-tetramethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-ethyl-3-(N,N-tetramethyleneamidino)urea

1-(2'-methyl-6'-chlorophenyl)-1-propyl-3-methylamidinourea

1-(2'-methyl-6'-chlorophenyl)-1-propyl-3-ethylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-methylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-ethylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-propylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-i-propylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-butylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-i-butylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-t-butylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-pentylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-hexylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-propargylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-allylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-methoxyethylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-benzyloxyethylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-phenethoxyethylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-(N,N-dimethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-3-(N,N'-dimethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-3-(N,N-diethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-3-(N,N'-diethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-3-(N-methyl-N'-ethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-3-(N-methyl-N-ethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-3-(N,N-tetramethyleneamidino)urea

1-(2'-methyl-6'-bromophenyl)-3-(N,N-pentamethyleneamidino)urea

1-(2'-methyl-6'-bromophenyl)-3-(N,N-hexamethyleneamidino)urea

1-(2'-methyl-6'-bromophenyl)-3-(N,N,N',N'-tetramethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-3-(N,N,N'-trimethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-methylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-ethylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-propylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-i-propylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-butylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-i-butylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-allylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-propargylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-methoxyethylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-benzyloxyethylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-phenethoxyethylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-(N,N-dimethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-(N,N'-dimethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-(N,N-diethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-(N,N'-diethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-(N,N,N'-trimethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-(N-methyl-N'-ethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-(N,N-tetramethyleneamidino)urea

1-(2'-methyl-6'-bromophenyl)-1-methyl-3-(N,N-pentamethyleneamidino)urea

1-(2'-methyl-6'-bromophenyl)-1-ethyl-3-methylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-ethyl-3-ethylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-ethyl-3-propylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-ethyl-3-i-butylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-ethyl-3-allylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-ethyl-3-propargylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-ethyl-3-methoxyethylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-ethyl-3-benzyloxyethylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-ethyl-3-(N,N-dimethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-1-ethyl-3-(N,N-pentamethyleneamidino)urea

1-(2'-methyl-6'-bromophenyl)-1-ethyl-3-(N,N,N'-trimethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-1-propyl-3-methylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-propyl-3-ethylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-propyl-3-propylamidinourea

1-(2'-methyl-6'-bromophenyl)-1-propyl-3-(N,N-dimethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-1-propyl-3-(N,N-tetramethyleneamidino)urea

1-(2'-methyl-6'-bromophenyl)-1-propyl-3-(N,N,N'-trimethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-3-methylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-ethylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-propylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-butylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-i-butylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-pentylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-allylamidinourea

1 -(2'-ethyl-6'-chlorophenyl)-3-propargylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-methoxyethylamidinourea

1(2'-ethyl-6'-chlorophenyl)-3-benzyloxyethylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-(N,N-dimethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-3-(N,N'-dimethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-3-(N,N-diethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-3-(N,N'-diethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-3-(N,N-tetramethyleneamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-3-(N,N-tetramethylene-N'-methylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-3-(N,N,N'-trimethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-3-(N,N,N',N'-tetramethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-methylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-ethylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-propylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-butylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-i-butylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-pentylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-allylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-propargylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-methoxyethylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-benzyloxyethylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-(N,N-dimethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-(N,N'-dimethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-(N,N-diethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-(N,N'-diethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-(N,N-tetramethyleneamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-(N,N-tetramethylene-N'-methylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-(N,N,N',N'-tetramethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-methyl-3-(N,N,N'-trimethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-methylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-ethylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-propylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-i-propylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-butylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-i-butylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-t-butylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-allylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-proparglyamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-cyclopropylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-methoxyethylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-benzyloxyethylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-(N,N-dimethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-(N,N'-dimethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-(N,N-diethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-(N,N'-diethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-(N-methyl-N'-ethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-(N,N,N'-trimethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-(N,N,N',N'-tetramethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-(N,N-tetramethyleneamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-ethyl-3-(N,N-tetramethylene-N'-methylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-propyl-3-methylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-propyl-3-ethylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-propyl-3-propylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-propyl-3-i-propylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-propyl-3-butylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-propyl-3-i-butylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-propyl-3-allylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-propyl-3-propargylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-1-propyl-3-(N,N-dimethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-1-butyl-3-methylamidinourea

1-(2'-methyl-6'-fluorophenyl)-3-methylamidinourea

1-(2',6'-dimethyl-4'-hydroxyphenyl)-3-methylamidinourea

1-(2',6'-diethyl-4'-hydroxyphenyl)-3-methylamidinourea

1-(2'-methyl-6'-chloro-4'-hydroxyphenyl)-3-methylamidinourea

1-(2'-methyl-6'-bromo-4'-hydroxyphenyl)-3-methylamidinourea

1-(2'-methyl-6'-fluoro-4'-hydroxyphenyl)-3-methylamidinourea

1-(2'-methyl-6'-ethyl-4'-hydroxyphenyl)-3-methylamidinourea

1-(2'-ethyl-6'-chloro-4'-hydroxyphenyl)-3-methylamidinourea

1-(2'-ethyl-6'-bromo-4'-hydroxyphenyl)-3-methylamidinourea

1-(2'-ethyl-6'-fluoro-4'-hydroxyphenyl)-3-methylamidinourea

1-(2',6'-dimethyl-4'-aminophenyl)-3-methylamidinourea

1-(2',6'-diethyl-4'-aminophenyl)-3-methylamidinourea

1-(2'-methyl-6'-ethyl-4'-aminophenyl)-3-methylamidinourea

1-(2'-methyl-6'-chloro-4'-aminophenyl)-3-methylamidinourea

1-(2'-methyl-6'-bromo-4'-aminophenyl)-3-methylamidinourea

1-(2'-methyl-6'-fluoro-4'-aminophenyl)-3-methylamidinourea

1-(2'-ethyl-6'-chloro-4'-aminophenyl)-3-methylamidinourea

1-(2'-ethyl-6'-bromo-4'-aminophenyl)-3-methylamidinourea

1-(2'-ethyl-6'-fluoro-4'-aminophenyl)-3-methylamidinourea

1-(2',6'-dimethyl-4'-acetylamino)-3-methylamidinourea

1-(2',6'-diethyl-4'-acetylamino)-3-methylamidinourea

1-(2'-methyl-6'-ethyl-4'-acetylamino)-3-methylamidinourea

1-(2'-methyl-6'-chloro-4'-acetylamino)-3-methylamidinourea

1-(2'-methyl-6'-bromo-4'-acetylamino)-3-methylamidinourea

1-(2'-methyl-6'-fluoro-4'-acetylamino)-3-methylamidinourea

1-(2'-ethyl-6'-chloro-4'-acetylamino)-3-methylamidinourea

1-(2'-ethyl-6'-bromo-4'-acetylamino)-3-methylamidinourea

1-(2'-ethyl-6'-fluoro-4'-acetylamino)-3-methylamidinourea

EXAMPLE 8

A. A solution of 200 g. of 2,6-dimethylaniline in 2 l. of ether iscooled in an ice bath and to this 88 g. of butyryl chloride in 150 ml.of ether is added dropwise (over 21/2 hours). A white precipitate formsand the reaction mixture is allowed to stir at 0° C. for 1 hour longerand then 15 hours at room temperature. The reaction mixture is thenevaporated in vacuo and the white solid residue is slurried in 1 l. ofwater, filtered and washed with water and dried to obtainN-butyryl-2,6-dimethylaniline (m.p. 134°-6° C.).

B. A suspension of 148.7 g. of N-butyryl-2,6-dimethylaniline in 1200 ml.of THF, under nitrogen, is cooled to about -10° C. with ice/MeOH bath.With contant cooling and stirring, 1200 ml. of 0.99 M borane in THF isadded dropwise over 4 hours maintaining the temperature about -5° C.After addition is complete, the mixture is allowed to warm to roomtemperature and then brought slowly to reflux and refluxed 6 hoursfollowed by 15 hours at room temperature. The reaction mixture is thencooled in ice and 500 ml. of 6 NHCl added dropwise with stirring. Thesolution is then evaporated in vacuo and the volume of residue isbrought to about 1 l. with water. This mixture is then cooled in ice andfiltered. The aqueous portion is extracted three times with 500 ml.portions of ether, cooled in an ice bath and made alkaline with sodiumhydroxide. The free base is extracted into ether with 3 × 400 ml.portions. The ether is dried over sodium sulfate, filtered, acidifiedwith ethereal HCl and the resulting solid filtered and dried. This isthen recrystallized from isopropanol (n-heptane) to giveN-butyl-2,6-dimethylaniline hydrochloride (m.p. 124°-131° C.).

C. To a suspension of 31.5 g. of N-butyl-2,6-dimethylaniline in 400 ml.of toluene is added 50 ml. of phosgene. The solution is heated to refluxand refluxed for 30 minutes. The solvent is then allowed to distill off(ca 350 ml.) and then cooled. The solution is evaporated in vacuo to alight oil which is then dissolved into hexane, filtered and the hexaneevaporated off in vacuo to give a milky oil which is then distilled togive 2,6-dimethyl-N-butylphenylcarbamoyl chloride (b.p. 105° C./0.1 mm)

When butyryl chloride in the above procedure is replaced by acetylchloride, propionyl chloride isopropionyl chloride, isobutyryl chloride,t-butyryl chloride or pentanoyl chloride, then the products preparedare:

2,6-dimethyl-N-ethylphenylcarbamoyl chloride

2,6-dimethyl-N-propylphenylcarbamoyl chloride

2,6-dimethyl-N-isobutylphenylcarbamoyl chloride

2,6-dimethyl-N-pentylphenylcarbamoyl chloride

When 2,6-dimethylphenyl-N-methyl-N-methylcarbamoyl chloride in Example7D is replaced with the above carbamoyl chloride then the productsprepared are

1-(2',6'-dimethylphenyl)-1-butyl-3-methylamidinourea nitrate

1-(2',6'-dimethylphenyl)-1-ethyl-3-methylamidinourea nitrate

1-(2',6'-dimethylphenyl)-1-propyl-3-methylamidinourea nitrate

1-(2',6'-dimethylphenyl)-1-i-propyl-3-methylamidinourea nitrate

1-(2',6'-dimethylphenyl)-1-i-butyl-3-methylamidinourea nitrate

1-(2',6'-dimethylphenyl)-1-t-butyl-3-methylamidinourea nitrate

EXAMPLE 9 1-(2,6-Diethyl-4-nitrophenyl)-3-methylamidinoureaHydrochloride

A. To a solution of 149.0 g (1.0 mole) of 2,6-diethylaniline in pyridine(500 ml) is added in portions at 0° C. 209.6 g (1.1 moles) ofp-toluenesulfonyl chloride. The reaction mixture is allowed to come toroom temperature and stir for three hours. The mixture is poured intocold aqueous 10% HCl and the crude sulfonamide solidified. Thesulfonamide is filtered, washed with water and crystallized from aceticacid to give N-(2,6-diethylphenyl)-p-toluenesulfonamide m.p. 130°-131°C.

B. To a solution of 115 ml nitric acid (d=1.42) in water (900 ml) areadded successively 129.9 g (0.43 moles) ofN-(2,6-diethylphenyl)-p-toluenesulfonamide, glacial acetic acid (900 ml)and sodium nitrite (3.2 g). The mixture is boiled on a steam bath for1.5 hours, then poured into ice water (2 l). The precipitate isfiltered, washed with water and air-dried to give crudeN-(2,6-diethyl-4-nitrophenyl)-p-toluenesulfonamide.

C. To 92.5 g (0.27 mole) of crudeN-(2,6-diethylphenyl)-p-toluenesulfonamide is added 300 ml of a mixtureof 300 ml of concentrated sulfuric acid and 30 ml of water and themixture heated at 90° C. for fifteen minutes. After cooling, the mixtureis poured into ice-water (2.5 l) and made basic with ammonia. Theprecipitated material is filtered and air-dried to give2,6-diethyl-4-nitroaniline.

D. Excess phosgene is bubbled into a warm solution of 21.5 g (0.11moles) of 2,6-diethyl-4-nitroaniline in toluene (250 ml). After theaddition, the mixture is heated to reflux and approximately 200 ml oftoluene are distilled. The remainder of the toluene is removed undervacuum and the remaining brown semi-solid is distilled under vacuum togive 2,6-diethyl-4-nitrophenylisocyanate, b.p. 135°-144° C./1 mm, as ayellow liquid which crystallized on standing.

E. To a stirred suspension of 7.3 g (30.0 mmol) of methylguanidinesulfate in tetrahydrofuran (80 ml) is added 4.8 g (60.0 mmol) of 50% w/wsodium hydroxide in water with continued stirring for one hour.Anhydrous sodium sulfate (10.0 g) is added and the mixture stirred anadditional hour after which 6.6 g (30.0 mmol) of2,6-diethyl-4-nitrophenylisocyanate is added and the resulting mixturestirred at room temperature over-night. The tetrahydrofuran is removedunder vacuum and the residue partitioned between water and chloroform.The layers are separated and the aqueous layer extracted with chloroform(1 × 100 ml). The combined extracts are dried (MgSO₄) and concentratedto give a yellow foam which is dissolved in methanol and acidified withHCl/MeOH. The methanol is removed under vacuum to give a yellow viscousoil which solidifies on scratching. Crystallization from methanol-ethylacetate gives 1-(2,6-diethyl-4-nitrophenyl)-3-methylamidinoureahydrochloride as a pale yellow solid, m.p. 173°-175° C.

When 2,6-diethylaniline in the above example is replaced by2,6-dimethylaniline, 2-methyl-6-ethylaniline, 2-methyl-6-chloroaniline,2-methyl-6-bromoaniline, 2-methyl-6-fluoroaniline,2-ethyl-6-chloroaniline, 2-ethyl-6-bromoaniline and2-ethyl-6-fluoroaniline, then the products prepared are

1-(2,6-dimethyl-4-nitrophenyl)-3-methylanilineurea hydrochloride

1-(2-methyl-6-ethyl-4-nitrophenyl)-3-methylanilineurea hydrochloride

1-(2-methyl-6-chloro-4-nitrophenyl)-3-methylanilineurea hydrochloride

1-(2-methyl-6-bromo-4-nitrophenyl)-3-methylanilineurea hydrochloride

1-(2-methyl-6-fluoro-4-nitrophenyl)-3-methylanilineurea hydrochloride

1-(2-ethyl-6-chloro-4-nitrophenyl)-3-methylanilineurea hydrochloride

1-(2-ethyl-6-bromo-4-nitrophenyl)-3-methylanilineurea hydrochloride

1-(2-ethyl-6-fluoro-4-nitrophenyl)-3-methylanilineurea hydrochloride

When the various guanidines of Examples 1-4 are used in place ofmethylguanidine sulfate in the above example, then the correspondingproduct is obtained.

EXAMPLE 10 1-(4-amino-2,6-diethylphenyl)-3-methylamidinoureaDihydrochloride

A mixture of 5.0 g (15.2 mmol) of1-(2,6-diethyl-4-nitrophenyl)-3-methylamidinourea hydrochloride and 5%paladium on carbon (500 mg) in absolute ethanol (175 ml) containingconcentrated hydrochloric acid (2 ml) is shaken under an atmosphere ofhydrogen (50 psi) for thirty minutes. The mixture is filtered through aCelite pad. To the filtrate is added HCl/MeOH and the alcohol is removedunder vacuum to give a yellow foam which is crystallized frommethanol-ethyl acetate to give1-(4-amino-2,6-diethylphenyl)-3-methylamidinourea dihydrochloride, m.p.218°-222° C. (dec).

When the nitro substituted amidinoureas of Example 9 are used in placeof 1-(2,6-diethyl-4-nitrophenyl)-3-methylamidinourea hydrochloride, thenthe products prepared are:

1-(2,6-dimethyl-4-aminophenyl)-3-methylamidinourea hydrochloride

1-(2-methyl-6-ethyl-4-aminophenyl)-3-methylanilineurea hydrochloride

1-(2-methyl-6-chloro-4-aminophenyl)-3-methylanilineurea hydrochloride

1-(2-methyl-6-bromo-4-aminophenyl)-3-methylanilineurea hydrochloride

1-(2-methyl-6-fluoro-4-aminophenyl)-3-methylanilineurea hydrochloride

1-(2-ethyl-6-chloro-4-aminophenyl)-3-methylanilineurea hydrochloride

1-(2-ethyl-6-bromo-4-aminophenyl)-3-methylanilineurea hydrochloride

1-(2-ethyl-6-fluoro-4-aminophenyl)-3-methylanilineurea hydrochloride

EXAMPLE 11 1-Propargylguanidine Sulfate

To a vigorously stirred suspension of 50.11 g. (0.18 moles) ofS-methylthiouronium sulfate in 100 ml. of water is added 20 g. (0.36moles) of propargyl amine under a blanket of nitrogen. The reactionmixture is stirred at room temperature for 4 hours and then warmedslowly to reflux and refluxed for 2 hours. The heat is removed and thereaction mixture allowed to stir at room temperature for 2 days. Themixture is then heated to reflux, filtered and then evaporated to neardryness. The residual oil is triturated in isopropanol and the solidwhich separates is filtered and dried. This material is then resuspendedin 1 l. of boiling methanol and water added dropwise until all of thesolid dissolves. The solution is then cooled in an ice bath and thesolid which separates is filtered, washed with methanol and dried togive 1-propargylguanidine sulfate (m.p. 200°-201° C.).

When allylamine is used in the above procedure in place of propargylamine, then the product obtained is allylguanidine.

When benzyloxyethylamine is used in the above procedure in place ofpropargyl amine, then the product obtained is benzyloxyethylguanidine.

When propargylamine in the above procedure is replaced by any suitableamine, then the corresponding guanidine is prepared.

EXAMPLE 12 1-(2',6'-Dimethylphenyl)-3-methyl-3-methylamidinourea

A quantity of 20 g. of 1-(2',6'-dimethylphenyl)-3,5-dimethylbiguanide isadded to 200 ml. of 10 hydrochloric acid and the mixture is refluxed for3 hours. The reaction mixture is then filtered hot and then chilled. Thematerial which separates is then filtered off and recrystallized fromisopropanol/water to obtain1-(2',6'-dimethylphenyl)-3-methyl-3-methylamidinourea hydrochloride.

The free base is prepared by dissolving the salt in 200 ml. of water andadding a 10% sodium hydroxide solution until alkaline. The reactionmixture is then extracted with chloroform which is dried and evaporatedto dryness to obtain1-(2',6'-dimethylphenyl)-3-methyl-3-methylamidinourea.

When the biguanides of Table I, below, are used in the above example inplace of 1-(2',6'-dimethylphenyl)-3,5-dimethylbiguanide, then thecorresponding product of Table II is obtained.

TABLE I

1-(2',6'-dimethylphenyl)-5-methylbiguanide

1-(2',6'-dimethylphenyl)-5,5-dimethylbiguanide

1-(2',6'-dimethylphenyl)-4,5-dimethylbiguanide

1-(2',6'-dimethylphenyl)-4,5,5-trimethylbiguanide

1-(2',6'-dimethylphenyl)-3-methylbiguanide

1-(2',6'-dimethylphenyl)-1-methylbiguanide

1-(2',6'-dimethylphenyl)-1,3-dimethylbiguanide

1-(2',6'-dimethylphenyl)-3,5-dimethylbiguanide

1-(2',6'-dimethylphenyl)-3,5,5-trimethylbiguanide

1-(2',6'-dimethylphenyl)-3,4,5-trimethylbiguanide

1-(2',6'-dimethylphenyl)-1,5-dimethylbiguanide

1-(2',6'-dimethylphenyl)-1,3,5-trimethylbiguanide

1-(2',6'-dimethylphenyl)-1,3,5,5-tetramethylbiguanide

1-(2',6'-dimethylphenyl)-1,3,4,5-tetramethylbiguanide

1-(2',6'-dimethylphenyl)-1,3,4,5,5-pentamethylbiguanide

1-(2',6'-diethylphenyl)-5-methylbiguanide

1-(2'-methyl-6'-methoxyphenyl)-5-methylbiguanide

1-(2'-methyl-6'-chlorophenyl)-5-methylbiguanide

1-(2'-methyl-6'-ethylphenyl)-5-methylbiguanide

1-(2'-methylphenyl)-5-methylbiguanide

1-(2',4',6'-trimethylphenyl)-5-methylbiguanide

1-(2'-methyl-4'-bromo-6'-chlorophenyl)-5-methylbiguanide

1-(2'-chloro-6'-fluorophenyl)-5-methylbiguanide

1-(2',5'-dichlorophenyl)-5-methylbiguanide

1-(2'-chloro-6'-bromophenyl)-5-methylbiguanide

1-(2'-chloro-5'-bromophenyl)-5-methylbiguanide

1-(2'-chloro-5'-fluorophenyl)-5-methylbiguanide

1-(2'-fluoro-5'-chlorophenyl)-5-methylbiguanide

1-(2'-fluoro-5'-bromophenyl)-5-methylbiguanide

1-(2',4',6'-triethylphenyl)-5-methylbiguanide

1-(2',4'-dimethyl-6'-ethylphenyl)-5-methylbiguanide

1-(2',6'-dimethyl-4'-ethylphenyl)-5-methylbiguanide

1-(2'-ethyl-6'-chlorophenyl)-5-methylbiguanide

1-(2'-ethylphenyl)-5-methylbiguanide

1-(2'-ethyl-4'-bromo-6'-chlorophenyl)-5-methylbiguanide

1-(2'-ethyl-6'-methoxyphenyl)-5-methylbiguanide

1-(2'-methyl-6'-ethoxyphenyl)-5-methylbiguanide

1-(2',6'-diethylphenyl)-3-methylbiguanide

1-(2'-methyl-6'-methoxyphenyl)-3-methylbiguanide

1-(2'-methyl-6'-chlorophenyl)-3-methylbiguanide

1-(2'-methyl-6'-ethylphenyl)-3-methylbiguanide

1-(2'-methylphenyl)-3-methylbiguanide

1-(2',4',6'-trimethylphenyl)-3-methylbiguanide

1-(2'-methyl-4'-bromo-6'-chlorophenyl)-3-methylbiguanide

1-(2'-chloro-6'-fluorophenyl)-3-methylbiguanide

1-(2',5'-dichlorophenyl)-3-methylbiguanide

1-(2',6'-dimethylphenyl)-5-ethylbiguanide

1-(2',6'-dimethylphenyl)-5-propylbiguanide

1-(2',6'-dimethylphenyl)-5-i-propylbiguanide

1-(2',6'-dimethylphenyl)-5-butylbiguanide

1-(2',6'-dimethylphenyl)-5-i-butylbiguanide

1-(2',6'-dimethylphenyl)-5-sec-butylbiguanide

1-(2',6'-dimethylphenyl)-5-t-butylbiguanide

1-(2',6'-dimethylphenyl)-5-pentylbiguanide

1-(2',6'-dimethylphenyl)-5-hexylbiguanide

1-(2',6'-dimethylphenyl)-5-heptylbiguanide

1-(2',6'-dimethylphenyl)-5-cyclopropylbiguanide

1-(2',6'-dimethylphenyl)-5-cyclobutylbiguanide

1-(2',6'-dimethylphenyl)-5-cyclopentylbiguanide

1-(2',6'-dimethylphenyl)-5-cyclohexylbiguanide

1-(2',6'-dimethylphenyl)-5-phenylbiguanide

1-(2',6'-dimethylphenyl)-5-benzylbiguanide

1-(2',6'-dimethylphenyl)-5-phenethylbiguanide

1-(2',6'-dimethylphenyl)-5,5-(N-methyl-3'-azapentamethylene)biguanide

1-(2',6'-dimethylphenyl)-5,5-(N-methyl-3'-azaheptamethylene)biguanide

1-(2',6'-dimethylphenyl)-5,5-(3'-oxopentamethylene)biguanide

1-(2',6'-dimethylphenyl)-5,5-(2'-thiatetramethylene)biguanide

1-(2',6'-dimethylphenyl)-5-methyl-5-ethylbiguanide

1-(2',6'-dimethylphenyl)-5,5-diethylbiguanide

1-(2',6'-dimethylphenyl)-5-methyl-5-benzylbiguanide

1-(2',6'-dimethylphenyl)-5,5-dibenzylbiguanide

TABLE II

3-(n-methylamidino)-1-(2,6-dimethylphenyl)urea

3-(N,N-dimethylamidino)-1-(2,6-dimethylphenyl)urea

3-(N,N'-dimethylamidino)-1-(2,6-dimethylphenyl)urea

3-(N,N,N'-trimethylamidino)-1-(2,6-dimethylphenyl)urea

3-methyl-3-amidino-1-(2,6-dimethylphenyl)urea

1-methyl-3-amidino-1-(2,6-dimethylphenyl)urea

1,3-dimethyl-3-amidino-1-(2,6-dimethylphenyl)urea

3-methyl-3-(N-methylamidino)-1-(2,6-dimethylphenyl)urea

3-methyl-3-(N,N-dimethylamidino)-1-(2,6-dimethylphenyl)urea

3-methyl-3-(N,N'-dimethylamidino)-1-(2',6'-dimethylphenyl)urea

1-methyl-3-(N-methylamidino)-1-(2',6'-dimethylphenyl)urea

1,3-dimethyl-3-(N-methylamidino)-1-(2',6'-dimethylphenyl)urea

1,3-dimethyl-3-(N,N-dimethylamidino)-1-(2',6'-dimethylphenyl)urea

1,3-dimethyl-3-(N,N'-dimethylamidino)-1-(2',6'-dimethylphenyl)urea

1,3-dimethyl-3-(N,N,N'-trimethylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-methylamidino)-1-(2',6'-diethylphenyl)urea

3-(N-methylamidino)-1-(2'-methyl-6'-methoxyphenyl)urea

3-(N-methylamidino)-1-(2'-methyl-6'-chlorophenyl)urea

3-(N-methylamidino)-1-(2'-methyl-6'-ethylphenyl)urea

3-(N-methylamidino)-1-(2'-methylphenyl)urea

3-(N-methylamidino)-1-(2',4',6'-trimethylphenyl)urea

3-(N-methylamidino)-1-(2'-methyl-4'-bromo-6'-chlorophenyl)urea

3-(N-methylamidino-)-1-(2'-chloro-6'-fluorophenyl)urea

3-(N-methylamidino)-1-(2',5'-dichlorophenyl)urea

3-(N-methylamidino)-1-(2'-chloro-6'-bromophenyl)urea

3-(N-methylamidino)-1-(2'-chloro-5'-bromophenyl)urea

3-(N-methylamidino)-1-(2'-chloro-5'-fluorophenyl)urea

3-(N-methylamidino)-1-(2'-fluoro-5'-chlorophenyl)urea

3-(N-methylamidino)-1-(2'-fluoro-5'-bromophenyl)urea

3-(N-methylamidino)-1-(2',4',6'-triethylphenyl)urea

3-(N-methylamidino)-1-(2',4'-dimethyl-6'-ethylphenyl)urea

3-(N-methylamidino)-1-(2',6'-dimethyl-4'-ethylphenyl)urea

3-(N-methylamidino)-1-(2'-ethyl-6'-chlorophenyl)urea

3-(N-methylamidino)-1-(2'-ethylphenyl)urea

3-(N-methylamidino)-1-(2'-ethyl-4'-bromo-6'-chlorophenyl)urea

3-(N-methylamidino)-1-(2'-ethyl-6'-methoxyphenyl)urea

3-(N-methylamidino)-1-(2'-methyl-6'-ethoxyphenyl)urea

3-methyl-3-amidino-1-(2',6'-diethylphenyl)urea

3-methyl-3-amidino-1-(2-methyl-6-methoxyphenyl)urea

3-methyl-3-amidino-1-(2'-methyl-6'-chlorophenyl)urea

3-methyl-3-amidino-1-(2'-methyl-6'-ethylphenyl)urea

3-methyl-3-amidino-1-(2'-methylphenyl)urea

3-methyl-3-amidino-1-(2',4',6'-trimethylphenyl)urea

3-methyl-3-amidino-1-(2'-methyl-4'-bromo-6'-chlorophenyl)urea

3-methyl-3-amidino-1-(2'-chloro-6'-fluorophenyl)urea

3-methyl-3-amidino-1-(2',5'-dichlorophenyl)urea

3-(N-ethylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-propylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-i-propylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-butylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-i-butylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-sec-butylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-t-butylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-pentylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-hexylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-heptylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-cyclopropylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-cyclobutylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-cyclopentylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-cyclohexylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-phenylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-benzylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-phenethylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N,N-pentamethyleneamidino)-1-(2',6'-dimethylphenyl)urea

3-[N,N-(N-methyl-3'-azapentamethylene)amidino]-1-(2',6'-dimethylphenyl)urea

3-[N,N-(N-methyl-3'-azaheptamethylene)amidino]-1-(2',6'-dimethylphenyl)urea

3-[N,N-(3'-oxopentamethylene)amidino]-1-(2',6'-dimethylphenyl)urea

3-[N,N-(2'-thiatetramethylene)amidino]-1-(2',6'-dimethylphenyl)urea

3-(N-methyl-N-ethylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N,N-diethylamidino)-1-(2',6'-dimethylphenyl)urea

3-(N-methyl-N-benzylamidino-1-(2',6'-dimethylphenyl)urea

3-(N,N-dibenzylamidino)-1-(2',6'-dimethylphenyl)urea

EXAMPLE 13

Ten thousand tablets for oral use, each containing 50 mg. of1-(2',6'-dichlorophenyl)-3-methylamidinourea hydrochloride, are preparedfrom the following types and amounts of material:

    ______________________________________                                        Ingredient:               Grams                                               ______________________________________                                        1 - (2',6'-dichlorophenyl)-3-methylamidinourea                                hydrochloride             500                                                 Lactose U.S.P.            350                                                 Potato Starch U.S.P.      346                                                 ______________________________________                                    

The mixture is moistened with an alcoholic solution of 20 grams ofstearic acid and granulated through a sieve. After drying, the followingingredients are added:

    ______________________________________                                        Ingredient:           Grams                                                   ______________________________________                                        Potato Starch U.S.P.  320                                                     Talcum                400                                                     Magnesium stearate    500                                                     Golloidal silicium dioxide                                                                           64                                                     ______________________________________                                    

The mixture is thoroughly mixed and compressed into tablets.

EXAMPLE 14

Five hundred ampoules each with two ml. of solution which contain 15 mg.of 1-(2-methyl-6-chlorophenyl)-3-methylamidinourea hydrochloride isprepared from the following types and amounts of materials:

    ______________________________________                                        Ingredient:              Grams                                                ______________________________________                                        1 - (2-methyl)-6-chlorophenyl)-3-methyl-                                      amidinourea hydrochloride                                                                              7.5                                                  Ascorbic acid             1                                                   Sodium bisulphite        0.5                                                  Sodium sulphite           1                                                   ______________________________________                                    

EXAMPLE 15

Capsules are prepared as follows:

15 g. of 1-(2,6-diethylphenyl)-3-methylamidinourea hydrochloride,

3 g. magnesium stearate,

2 g. of finely divided silica sold under the trademark CAB-O-SIL byGodfrey L. Cabot, Inc., Boston, Mass.,

and

369 g. of lactose.

The ingredients are thoroughly mixed with each other and the mixture isfilled in gelatin capsules. Each capsule contains 500 mg. of thecomposition and thus 15 mg. of 1-(2,6-diethylphenyl)-3-methylamidinoureahydrochloride.

EXAMPLE 16

50 g. of 1-(2',6'-dimethylphenyl)-3-methylamidinourea hydrochloride, 5g. of propyl p-hydroxybenzoate are dissolved and dilluted to 5000 cc.with twice distilled water after the addition of modified Sorensenbuffer solution in an amount sufficient to adjust the pH-value to a pHof 6.0. Sodium chloride is dissolved therein in an amount sufficient torender the resulting solution isotonic. The final solution is passedthrough a bacteriological filter and the filtrate is autoclaved at 120C. for 15 minutes to yield a parenterally applicable solution whichcontains 50 mg. of 1-(2',6'-dimethylphenyl)-3-methylamidinoureahydrochloride in 5 cc.

We claim:
 1. A method for producing local anesthetic action in a patientwhich comprises administering parenterally to said patient an effectivedaily dosage of between 0.1 and 70 mg/kg of body weight of said patienta compound of the formula: ##STR11## where: R₂, R₃, R₄, R₅ and R₆ may bethe same or different and are:hydrogen, halo, loweralkyl,haloloweralkyl, nitro, amino, acylamino or loweralkoxy; R_(n) ishydrogen orloweralkyl; and R₇, r₈, r₉ and R₁₀ are:hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylloweralkyl,alkoxyloweralkyl, aralkoxyloweralkyl or aralkyl; and the non-toxic acidaddition salts thereof.
 2. The method of claim 1 where:R₂ is hydrogen,methyl or ethyl; R₃ and R₅ are hydrogen; R₄ is hydrogen, methyl, ethyl,chloro or bromo; R₆ is hydrogen,methyl, ethyl, nitro, methoxy, ethoxy,chloro, bromo or fluoro; R_(n) is hydrogen,methyl or ethyl, and R₇, r₈,r₉ and R₁₀ are hydrogen, methyl,ethyl, propyl, i-propyl, butyl, i-butyl,sec-butyl, t-butyl, pentyl, hexyl, heptyl, allyl, propargyl,methoxyethyl, ethoxyethyl, benzyloxyethyl; provided R₇, R₈, R₉ and R₁₀are not all hydrogen at the same time.
 3. The method of claim 2 where:R₂and R₆ are diloweralkyl; R_(n), R₃, R₄, R₅, R₈, R₉ and R₁₀ are hydrogenand R₇ is loweralkyl.
 4. The method of claim 3 where:R₂, r₆ and R₇ aremethyl.
 5. The method of claim 3 where:R₂ and R₆ are ethyl and R₇ ismethyl.
 6. A method for producing local anesthetic action in a patientwhich comprises administering topically to said patient a compositioncontaining, in the range of 0.1-10% by weight of said composition, acompound of the formula: ##STR12## where: R₂, R₃, R₄, R₅ and R₆ may bethe same or different and are:hydrogen, halo, loweralkyl,haloloweralkyl, nitro, amino, acylamino or loweralkoxy R_(n) is hydrogenorloweralkyl; and R₇, r₈, r₉ and R₁₀ are:hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkylloweralkyl,alkoxyloweralkyl, aralkoxyloweralkyl or aralkyl; and the non-toxic acidaddition salts thereof.
 7. The method of claim 6 where:R₂ is hydrogen,methyl or ethyl; R₃ and R₅ are hydrogen; R₄ is hydrogen, methyl, ethyl,chloro or bromo; R₆ is hydrogen;methyl, ethyl, nitro, methoxy, ethoxy,chloro, bromo or fluoro; R_(n) is hydrogen,methyl or ethyl, and R₇, r₈,r₉ and R₁₀ are hydrogenmethyl, ethyl, propyl, i-propyl, butyl, i-butyl,sec-butyl, t-butyl, pentyl, hexyl, heptyl, allyl, propargyl,methoxyethyl, ethoxyethyl, or benzyloxyethyl; provided R₇, R₈, R₉ andR₁₀ are not all hydrogen at the same time.
 8. The method of claim 7where:R₂ and R₆ are diloweralkyl; R_(n), R₃, R₄, R₅, R₈, R₉ and R₁₀ arehydrogen and R₇ is loweralkyl.
 9. The method of claim 8 where:R₂, r₆ andR₇ are methyl.
 10. The method of claim 8 where:R₂ and R₆ are ethyl andR₇ is methyl.